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Epilepsy and genetic in Rett syndrome: A review

Abstract Introduction Rett syndrome (RTT) is a severe X‐linked neurodevelopmental disorder that primarily affects girls, with an incidence of 1:10,000–20,000. The diagnosis is based on clinical features: an initial period of apparently normal development (ages 6–12 months) followed by a rapid decline with regression of acquired motor skills, loss of spoken language and purposeful hand use, onset of hand stereotypes, abnormal gait, and growth failure. The course of the disease, in its classical form, is characterized by four stages. Three different atypical variants of the disease have been defined. Epilepsy has been reported in 60%–80% of patients with RTT; it differs among the various phenotypes and genotypes and its severity is an important contributor to the clinical severity of the disease. Methods In this manuscript we reviewed literature on RTT, focusing on the different genetic entities, the correlation genotype–phenotype, and the peculiar epileptic phenotype associated to each of them. Results Mutations in MECP2 gene, located on Xq28, account for 95% of typical RTT cases and 73.2% of atypical RTT. CDKL5 and FOXG1 are other genes identified as causative genes in atypical forms of RTT. In the last few years, a lot of new genes have been identified as causative genes for RTT phenotype. Conclusions Recognizing clinical and EEG patterns in different RTT variants may be useful in diagnosis and management of these patients.

practice, gene analysis is performed to confirm it and to determine the causative mutation. Most children with RTT are the born from a normal pregnancy and delivery (Dolce, Ben-Zeev, Naidu, & Kossoff, 2013). An initial period of apparently normal development (ages 6-12 months) is followed by a period of rapid decline with regression of acquired motor skills, loss of spoken language and purposeful hand use, onset of hand stereotypes, abnormal gait, and growth failure. This regression is sometimes sudden and often rapid, occurring in the time span of weeks to months and usually this period is associated with severe sleep disturbances, irritability, and poor eye contact (Dolce et al., 2013). According to revised diagnostic criteria for RTT by Neul et al., in classic RTT, a period of regression followed by recovery or stabilization and the presence of four main criteria and two exclusion criteria are required for diagnosis ; Table 1). With regard to postnatal deceleration in head growth, it is an early sign, which begins between 2 and 4 months of age (Dolce et al., 2013). Nevertheless, it is not found in all patients with typical RTT (Hagberg, Stenbom, & Witt Engerstrom, 2000); for this reason, it has been eliminated from the necessary criteria, but it is considered nowadays a preamble to them, as a feature that should raise suspicion for the diagnosis .
The course of the disease, in its classical form, is characterized by four stages with an apparently normal early psychomotor development in the first 6 months of life (Hagberg et al., 2002; Table 2).
In addition to the classical form, it has been recognized that some individuals present with many of the clinical features of RTT but do not have all the features of this condition. These have been termed "variant" or "atypical" RTT: the preserved speech variant (Zappella variant), the congenital variant (Rolando variant), and the early seizure variant (Hanefeld variant). For the diagnosis of atypical or variant RTT, a period of regression followed by recovery or stabilization and at least two of the four main criteria and five of the 11 supportive criteria are needed  Table 3).
According to the data of the United States RTT National History Study, on a sample of 819 patients enrolled, 85.4% met diagnostic criteria for classic RTT and 14.6% for RTT variants .
Zappella variant is a clinical variant characterized by regression at 1-3 years, prolonged plateau phase, milder compromission of purposeful hand use, and milder intellectual disability. The distinctive feature of this variant is the recovery of language after regression, at a mean age of 5 years, along with the rarity of epilepsy. MeCP2 gene mutations are found in majority.
Rolando variant (or congenital variant) is characterized by severe psychomotor delay with inability to walk, severe postnatal microcephaly, regression in first 5 months, lack of typical RTT eye gaze, autonomic abnormalities (small cold hands and feet, peripheral vasomotor disturbances, breathing abnormalities while awake), and movement abnormalities (tongue stereotypes, jerky movements of the limbs).
Mutations in MECP2 gene are rarely found in this variant, which is closely linked to mutations in FOXG1 (Forkhead box protein G1) gene.
Hanefeld variant is characterized by early onset of seizures (infantile spasms and refractory myoclonic epilepsy) before regression, usually before 5 months of life. Other typical RTT features are less frequent. Also, in this variant, mutations in the MECP2 gene are rarely found, as it is characterized by mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene, a regulator of MECP2 which also has important roles in neuronal maturation and brain development.
RTT is the major cause of mental retardation in females after Down syndrome (Krajnc, 2015), but it has also been documented in normal female carriers, in females with variant forms, and in some males with Klinefelter syndrome, fatal encephalopathy, familial X-linked mental retardation, and males with features of RTT . As an X-linked disorder, RTT was considered lethal in males; however, males with clinical features of RTT were reported even before the discovery of the causal gene. Wan et al. first described a male patient with a congenital neonatal encephalopathy and mutation in MECP2, who died at 1 year of age . Males with MECP2 mutations fall into four categories: severe neonatal encephalopathy and infantile death; classical RTT; less severe neuropsychiatric symptoms; MECP2 duplication syndrome (Imessaoudene et al., 2001;Jülich, Horn, Burfeind, Erler, & Auber, 2009;Kyle, Vashi, & Justice, 2018;Meloni et al., 2000;Ramocki et al., 2009;Schwartzman, Bernardino, Nishimura, Gomes, & Zatz, 2001;Topҫu et al., 2002;Van Esch et al., 2005;Zeev et al., 2002;

| CURRENT UPDATE IN THE G ENE TI C OF RE T T SYNDROME
It is well established that mutations in MECP2 gene, located on Xq28, account for 95% of typical RTT cases and 73.2% of atypical RTT (Ehrhart, Sangani, & Curfs, 2018). MECP2 is a protein ubiquitously present throughout all human tissues and particularly abundant in neurons and astrocytes in the brain. It is expressed at low levels prenatally and increases during neuronal maturation and synaptogenesis suggesting an important role in neuronal activity and plasticity (Cohen et al., 2003;Jung et al., 2003;Samaco, Nagarajan, Braunschweig, & LaSalle, 2004) of all mutations (Kyle et al., 2018) and R168X is the most common one; C-terminal deletions account for 8% and large deletions for another 5% (Neul et al., 2008).
Despite the wide spectrum of MECP2 mutations and the variety of phenotype severity, there are no clear genotype-phenotype correlations (Guerrini et al., 2012). Some studies in literature have proposed a correlation between genotype and clinical features in RTT patients (Cuddapah et al., 2014;Neul et al., 2008). Early truncating mutations such as R168X, R255X, and R270X and large insertions and deletions cause the most severe phenotype. Missense mutations such as R133C and R306C, late truncating mutations such as those in R294X and others in the 3' end are associated with the mildest phenotype. Despite this, phenotype variations commonly occur between patients with the same mutation.
Some possible explanation has been proposed, as differences in X chromosome inactivation (Ehrhart et al., 2018;Knudsen et al., 2006) and the presence of a second gene mutation, acting as modifier, alleviating or enhancing the phenotype outcome (Zeev et al., 2002).
CDKL5 is a gene located on Xp22 and code for a ubiquitous protein, mainly expressed in the brain, thymus, and testes, with a role in neuronal maturation (Guerrini et al., 2012;Rusconi et al., 2008).
Several mutations in the CDKL5 gene have been identified: point mutations, sequence variations resulting in missense, nonsense, splice and frameshift mutations, microdeletions, and larger rearrangements (Guerrini et al., 2012). CDKL5 is involved in the early seizure variant of RTT Scala et al., 2005).
FOXG1 is a transcriptional repressor involved in neuronal differentiation and highly expressed in the developing brain, whose gene is located on chromosome 14q12. Mutations in FOXG1 are responsible for the congenital variant of RTT (Ariani et al., 2008

| EPILEPSY IN RE T T SYNDROME
Epilepsy has been reported in 60%-80% of patients with RTT, differing among the various phenotypes and genotypes. Incidence is higher in patients with early onset RTT and more severe developmental disabilities (greater impairment of ambulation, hand use, and communication) . On the other hand, the severity of epilepsy is an important contributor to the clinical severity of RTT phenotype (Krajnc, 2015). Seizures seem to occur earlier in those patients who do not have MECP2 mutations (Jian et al., 2006).

| Epilepsy on MECP2-positive patients
With regard to classical form, seizures usually appear in the II or III stage of the disease, with the highest frequency occurring between 7 and 12 years (Krajnc, 2015).
Reviewing literature, severe mutations in MECP2 gene, such as large deletions, early truncating, and missense mutations in the methyl-binding domain or the nuclear localizing segment seem to be associated with earlier or more sever epilepsy, whereas milder mutations such as late truncating or C-terminal deletions seem to have a protective effect on epilepsy onset (Jian et al., 2006(Jian et al., , 2007Nectoux et al., 2008;Pintaudi et al., 2010).

| Epilepsy on FOXG1-positive patients
Severe early onset epilepsy has been reported as main features of the FOXG1-related phenotype (Guerrini et al., 2012). Kortüm et al. have described 11 patients carrying mutations in FOXG1 gene documenting tonic, generalized tonic-clonic and partial seizures, with onset between 3 months and 6 years (Kortüm et al., 2011).
Moreover, the association between 14q12 duplication including FOXG1 and infantile spasms has been documented (Striano et al., 2011), suggesting that overexpression of FOXG1 could have a specific role in the pathogenesis of infantile spasms.

| EEG FIND ING S
In literature, there are few reports of the characteristics EEG findings in patients with Rett syndrome, especially with regard to atypical variants (Figure 1).  (Dolce et al., 2013;Moser, Weber, & Lutschg, 2007).

| EEG on MECP2-positive patients
EEG findings that have been described as correlate of these ictal events are bilateral and synchronous initial flattening, followed by repetitive sharp waves and spikes; generalized ictal patterns in neonates or very young infants, atypical hypsarrhythmia, slowing background with multifocal interictal discharges, and suppression burst pattern (Grosso et al., 2007;Guerrini et al., 2012;Melani et al., 2011).

| EEG on CDKL5-positive patients
Limited information is available regarding the precise electroclinical phenotype in epileptic patients with mutations in CDKL5 gene.

| EEG on FOXG1-positive patients
To our knowledge, there are few reports concerning EEG findings in patients with RTT phenotype associated with FOXG1 mutations. Available EEG data only report focal and multifocal abnormalities in patients with tonic, generalized tonic-clonic and complex partial seizures (Guerrini et al., 2012;Kortüm et al., 2011).

| CON CLUS IONS
Rett syndrome is a truly complex neurological disorder, whose diagnostic criteria are based on phenotypic description. In addition to the classical form, a heterogeneous spectrum of phenotypes identifies those forms called "atypical Rett". Nowadays, it seems more correct to consider this broad spectrum of neurological disorders as the expression of a complex encephalopathy. Many efforts have been made to understand the molecular bases that underlie all different clinical phenotypes of RTT. With the increase of knowledge, especially thanks to recent genetic advances, many new genes have been identified as causative for RTT phenotype, in addition to MECP2, CDKL5, and FOXG1.
Epilepsy is a prominent symptom in RTT and it substantially contributes to the severity of the disease. Some genotypes are reported to be more frequently associated with epilepsy and even with a drug-resistant course. Recognizing clinical and EEG patterns in different RTT variants may be useful in diagnosis and management of these patients.
Long-term video EEG is surely a useful diagnostic tool which allows to differentiate between nonepileptic paroxysmal events and real epileptic seizures, to further classify seizure semiology and finally choice the most appropriate drug treatment. On the other hand, the identification of individual genetic background allows to diagnose the disorder properly and is helpful for treatment, not only for the genetic counseling.
In this manuscript, we aimed to clear-up the long-standing misunderstanding of differential diagnosis between Rett syndrome associated with MECP2 mutations and Rett-like phenotype of other neurodevelopmental diseases associated with different emerging genes.
Comparative studies with large cohorts of patients are needed to better understand the relationship between genotype and phenotype and correctly diagnose and treat these patients.
F I G U R E 1 EEG pattern of (a) a classical Rett syndrome, (b) a child with FOXG1 microduplication and epileptic spasms and microcephaly, (c) a 4-month CDKL5 girl with tonic/vibratory seizure followed by a cluster of spasms and clonic jerks