Rett Syndrome and the MECP2-CDKL5-FOXG1 Spectrum

Literature and regulatory information updated: 6 October 2026.

Classical and atypical Rett syndrome (MECP2), severe neonatal encephalopathy and PPM-X syndrome in males, MECP2 duplication syndrome, CDKL5 deficiency disorder and FOXG1 syndrome

0. Initial Reference Table

The sources for the table are the GeneReviews chapters for each condition, the Orphanet and OMIM records, the systematic prevalence review and the regulatory documents cited throughout the text [1–11]; the rows on the French protocol and the reference network are based on the four national diagnosis and care protocols of the Haute Autorité de Santé and on the websites of the European networks [12–16].

1. Introduction

Rett syndrome is a severe neurodevelopmental disorder affecting almost exclusively females, characterised by an initial period of apparently normal development followed by regression of language and purposeful hand use, the emergence of hand stereotypies, gait abnormalities and autonomic dysfunction, and subsequent long-term stabilisation [1,17]. In the Brazilian reference literature, it is considered the second cause of intellectual disability in females after Down syndrome [18]. The scope of this article is, however, broader than the classical form: it covers the allelic spectrum of MECP2 (with opposite phenotypes depending on whether there is loss of function or increased dosage) and two conditions classified for years as atypical Rett variants that are now separate entities, CDKL5 deficiency disorder and FOXG1 syndrome [3,4].

The history of the condition began in 1966, when the Austrian paediatrician Andreas Rett described, in an article published in Wiener Medizinische Wochenschrift, girls with a syndrome of cerebral atrophy and stereotyped hand movements, which he incorrectly attributed to hyperammonaemia [19]. The description remained little known until 1983, when Bengt Hagberg, Jean Aicardi, Karin Dias and Ovidio Ramos published in Annals of Neurology a series of 35 girls from three countries with “a progressive syndrome of autism, dementia, ataxia and loss of purposeful hand use”, to which they gave Rett's name: normal development until 7–18 months was followed by stagnation and, over approximately a year and a half, rapid deterioration of higher functions, with loss of purposeful hand use, truncal ataxia, acquired microcephaly and autistic behaviour, followed by apparent stability for decades, with spastic paraparesis, vasomotor abnormalities of the lower limbs and epilepsy [20]. The authors noted that exclusive female involvement suggested a dominant mutation on an X chromosome, with inviability of male hemizygous conceptuses, a hypothesis partly confirmed by molecular genetics [20].

The molecular phase began in 1999, when Ruthie Amir, Huda Zoghbi and colleagues identified pathogenic variants in MECP2, located at Xq28 and encoding methyl-CpG-binding protein 2 (MeCP2), as the cause of Rett syndrome [21]. In the same year, descriptions followed of recurrent variants at CpG dinucleotides and familial cases with asymptomatic carrier mothers owing to skewed X-chromosome inactivation [22]. The 2007 review by Chahrour and Zoghbi summarised the transition “from the clinic to neurobiology” in this disorder [23]. In 2007, the demonstration by Guy, Bird and colleagues that Mecp2 reactivation in symptomatic mice reverses the neurological phenotype established that Rett syndrome is not an irreversible neurodegenerative disease, providing the basis for the development of current gene therapies [24].

In 2004, two independent groups associated variants in CDKL5 (then called STK9) with a severe encephalopathy with infantile spasms in girls, a phenotype overlapping the early-seizure Rett variant described by Hanefeld [25,26]. In 2005, Van Esch and colleagues showed that duplication of the MECP2 region is a common cause of severe intellectual disability with progressive neurological symptoms in males, establishing that neuronal function is sensitive to MeCP2 dosage in both directions [27]. In 2008, Ariani and colleagues demonstrated that FOXG1 causes the congenital Rett syndrome variant [28], and in 2011 Kortüm and colleagues defined the core phenotype of FOXG1 syndrome and proposed that it be considered a separate entity [29]. The 2010 revision of diagnostic criteria and nomenclature by the RettSearch consortium consolidated the distinction between typical and atypical Rett syndrome [30], and the 2022 classification of the International League Against Epilepsy (ILAE, International League Against Epilepsy) designated CDKL5 deficiency disorder as CDKL5-related developmental and epileptic encephalopathy (CDKL5-DEE) [31,32]. The name CDKL5 Deficiency Disorder was recognised in the World Health Organization classification on 1 October 2020; synonyms still found in databases include early infantile epileptic encephalopathy type 2 and X-linked infantile spasms type 2 [14].

The last decade has changed the therapeutic landscape. In 2022 ganaxolone (Ztalmy®) became the first drug approved specifically for seizures in CDKL5 deficiency disorder [33,34], in March 2023 trofinetide (Daybue®) became the first drug approved by the US FDA (Food and Drug Administration) for Rett syndrome [35,36], and in August 2026 the European Commission authorised trofinetide in the European Union under the brand name Daybu® [37]. In parallel, two gene therapies using adeno-associated virus serotype 9 (AAV9) vectors and an antisense oligonucleotide for MECP2 duplication are in clinical trials [38–40].

2. Molecular Genetics and Pathophysiology

2.1. MECP2: structure, function and dosage sensitivity

The MECP2 gene is located at Xq28, is subject to X-chromosome inactivation and encodes MeCP2, an abundant nuclear protein that binds symmetrically methylated CpG dinucleotides and also 5-hydroxymethylcytosine, recruiting the SIN3A corepressor and histone deacetylases to maintain transcriptional repression of inactive genes [1,17,23]. MeCP2 has four main functional domains: the methyl-CpG-binding domain (MBD, methyl binding domain), which binds DNA at symmetrically methylated CpGs in chromatin; the transcriptional repression domain (TRD, transcription repression domain), which recruits proteins mediating repression; the AT hooks (A-T hook), basic residues binding adenine- and thymine-rich DNA; and the WW domain, conserved in the C-terminal region [1]. In addition to repression, MeCP2 participates in splicing and long-range chromatin remodelling and can act as a transcriptional activator; its loss leads to epigenetic chromatin aberrations, including possible loss of imprinting [1]. Neuronal MeCP2 expression is low during embryogenesis, rises during postnatal development and peaks with neuronal maturation; it is dispensable in stem cells and essential for postnatal brain maturation and synaptic refinement. This timing explains apparently normal development in the first months and subsequent regression [1,2].

MeCP2 is a protein with strict dosage sensitivity in both directions. ClinGen dosage curation assigns MECP2 a haploinsufficiency score of 3 (sufficient evidence) and a triplosensitivity score of 0, but duplication of the entire gene is a well-defined disease, MECP2 duplication syndrome; the same gene therefore causes two diseases with opposite mechanisms that must not be confused [2,41].

There are two isoforms: MECP2_e1 (NM_001110792, exons 1, 3 and 4; 498 amino acids; current version .2, MANE Select), expressed much more highly in the brain, and MECP2_e2 (NM_004992, exons 2, 3 and 4; 486 amino acids; current version .4, MANE Plus Clinical), which differ at the N-terminus because they use alternative initiation codons [1]. Pathogenic variants in exon 1 are rare (initiation codon p.Met1?, p.Ala2 and frameshift variants), and a variant in the exon 2 initiation codon has been described [1]. Most pathogenic variants lie in the region encoding the MBD (exons 3 and 4; amino acids 90–174 of the e2 isoform) and impair binding to target DNA; several recurrent nonsense variants lie in the TRD (exon 4; amino acids 219–322), and many frameshift variants eliminate the C-terminus (3′ region of exon 4) [1]. Recurrent nonsense (p.Arg168Ter, p.Arg255Ter) and missense (p.Arg106Trp, p.Arg306Cys) variants result from cytosine→thymine transitions at CpG dinucleotides [22]; de novo variants usually arise on the paternal X chromosome [17].

The table summarises the MECP2 variants highlighted in GeneReviews [1]; correspondence with the MANE Select transcript results from the additional 12 amino acids (36 nucleotides) at the N-terminus of the e1 isoform, as shown in the ClinVar records for p.(Thr170Met), p.(Arg180Ter) and p.(Ala152Val) [42]; variant interpretation should follow the ClinGen Rett and Angelman-like disorders expert panel specifications (version 5.0.0), which adapt the ACMG/AMP (American College of Medical Genetics and Genomics / Association for Molecular Pathology) rules for MECP2, CDKL5 and FOXG1 [1,3,4]. In a Brazilian series of 105 patients, 68% had classical Rett syndrome and pathogenic point variants were found in 64.1% of all patients and 70.42% of patients with the classical phenotype (screening by coding-region sequencing, without deletion analysis) [43]. According to the same Brazilian teaching source, missense variants are generally associated with milder presentations and nonsense variants with more severe presentations [18].

2.2. X-chromosome inactivation and expression in heterozygotes

Approximately 90% of affected girls have random X inactivation [17]. Skewed inactivation favouring the normal allele explains heterozygous mothers with no or mild manifestations, carrier sisters without signs and phenotypes limited to mild learning difficulties; in the families described, less extreme skewing is associated with milder phenotypes [1,17]. Genotype–phenotype correlations are therefore inconsistent [1].

2.3. MECP2 disorders in males

In hemizygous males, MECP2 loss of function most often produces severe neonatal encephalopathy, with death frequently before two years; in X-linked dominant inheritance generally, affected male fetuses may be lost spontaneously or die in the neonatal period [1,44]. Milder phenotypes include PPM-X syndrome (pyramidal signs, parkinsonism and macro-orchidism, with episodic psychosis) associated with p.(Ala140Val), and syndromic or non-syndromic intellectual disability [1,45]. Boys meeting classical Rett criteria usually have a 47,XXY karyotype or postzygotic somatic mosaicism; among 354 boys with unexplained intellectual disability, only one potentially pathogenic variant was found (0.28%), so the true rate in male non-syndromic ID is very low [17]. A Brazilian case of a Rett phenotype in a boy with a 47,XXY karyotype is described in section 10 [46].

2.4. MECP2 duplication syndrome

MECP2 duplication syndrome results from Xq28 duplications including the entire MECP2; most are interstitial duplications of 0.2 to 2.2 Mb (according to Smith's) or 0.3 to 4 Mb (according to GeneReviews), but they may also result from unbalanced translocations with an autosome or the Y chromosome [2,47]. The smallest region of overlap contains MECP2, responsible for the neurological and dysmorphic phenotype, and IRAK1, encoding interleukin-1 receptor-associated kinase 1 and probably responsible for recurrent infections [47]. Duplication of adjacent FLNA has been proposed as a cause of severe chronic intestinal pseudo-obstruction and bladder dysfunction, although constipation is common even without FLNA duplication; GDI1 may explain microcephaly in larger duplications [47,48]. The mechanism is increased protein expression: mouse models and human induced pluripotent stem cell-derived neurons with the duplication show abnormal morphology and electrophysiological behaviour [2]. There is a copy-number effect, with more severe phenotypes in triplications [2,45,47]. In women with interstitial duplication, X inactivation is usually skewed against the duplicated X; in duplications due to X–autosome translocation or insertion elsewhere in the genome there is no effective skewing and the female phenotype is severe [2]. Distinct from this condition is int22h1/int22h2-mediated Xq28 duplication syndrome, a 0.5 Mb duplication telomeric to MECP2 (154.1–154.6 Mb), with milder cognitive impairment and without infantile hypotonia, spasticity or epilepsy [2].

2.5. CDKL5

CDKL5 (Xp22.13) encodes cyclin-dependent kinase-like 5, a 115 kDa serine-threonine kinase of the CMGC family, expressed throughout the central nervous system, mainly in neurons, where it is located in dendritic spines of excitatory synapses and in the nucleus; its expression increases postnatally [3]. It interacts with PSD-95, gephyrin, NGL-1, Shootin1, actin, microtubule-binding proteins (MAP1 and EB2, which it directly phosphorylates), MeCP2, DNMT1, AMPH1 and HDAC4 [3]. CDKL5 loss reduces the number of excitatory synapses, PSD-95 and synapsin, with loss of AMPA receptors (GluA2) and increased NMDA receptors (GluN2B) [3]. The mechanism is loss of function, with pathogenic missense variants concentrated in the kinase domain; ClinGen assigns a haploinsufficiency score of 3 and a triplosensitivity score of 0 [3,41]. Whether the phenotype results from chronic CDKL5 dysfunction, compensatory effects during a critical developmental period or intractable epilepsy is not established [3]. CDKL5 duplications and gain-of-function missense variants are associated with different and generally milder manifestations, so a CDKL5 duplication should not be interpreted as CDD [3].

There are three critical laboratory considerations. First, transcript NM_001323289, the most highly expressed in the brain, contains 170 nucleotides at the 3′ end of the last exon that are non-coding in historically used transcripts (NM_003159 and NM_001037343), and pathogenic variants in that region have been missed by clinical laboratories [3]. Second, mosaic variants occur (nucleotide variants, deletions and inversions, the latter detected by array CGH and optical genome mapping), so sequencing depth influences yield [3]. Third, intronic variants affecting splicing and deletions in the 5′ untranslated region have been described, justifying consideration of genome sequencing when the panel or exome is negative and the phenotype is suggestive [3]. Larger contiguous deletions may add manifestations, such as features of Nance–Horan syndrome in a deletion including CDKL5 and NHS [3].

2.6. FOXG1

FOXG1 (14q12) has a single coding exon and belongs to the forkhead family; it encodes a transcriptional repressor expressed in the fetal and adult brain, essential for development of the telencephalon and its derived structures (cortex, hippocampus, basal ganglia), neocortical progenitor proliferation and differentiation, neocortical lamination, formation of the postnatal hippocampal dentate gyrus and interneuron development [4]. Intragenic deletions and truncating variants cause loss of function; pathogenic missense variants probably cause a lesser degree of loss; ClinGen assigns a haploinsufficiency score of 3 [4,41]. The structural consequence is visible on neuroimaging (abnormalities of the corpus callosum, gyration and fornices, hypoplasia of the basal ganglia and frontal lobes), without a biochemical marker [4,49]. In experimental models, FOXG1 overexpression leads to dendritic elongation and its reduction decreases axonal and dendritic length, dendritic branching and spine density; the mechanism of FOXG1 duplications, which cause a different phenotype, remains unclear [4]. Contiguous deletions including PRKD1 and NOVA1 add facial dysmorphism (prominent metopic suture, epicanthic folds, bulbous nasal tip, tented upper lip, everted lower lip and large ears) [4,17].

3. Clinical Spectrum and Manifestations by Organ System

3.1. Classical (typical) Rett syndrome

In the classical form, psychomotor development appears normal for the first 6 to 18 months, followed by a short period of stagnation and then rapid regression of language and motor skills, followed by prolonged stability [1]. During regression, stereotyped repetitive hand movements replace purposeful use; additional features include screaming episodes and inconsolable crying, autistic behaviours, panic-like attacks, bruxism, episodic apnoea and/or hyperpnoea, gait ataxia and apraxia, tremor, seizures and acquired microcephaly [1]. Although early development is described as normal, parents frequently identify subtle differences from siblings retrospectively [1]. The Brazilian source describes the syndrome as a progressive encephalopathy with four stages in its classical form (68% of cases in the cited series), whereas GeneReviews emphasises long-term stability after regression; these perspectives can be reconciled by recognising that regression is time-limited and motor and orthopaedic complications evolve throughout life [1,18,43].

The staging table reproduces the table in the Brazilian source [18]. In the series by Cass and colleagues (87 females aged 2 to 44 years), almost all adults had fixed joint deformities and scoliosis; growth delay was almost universal in older children; feeding difficulties increased until middle childhood and then stabilised; mobility improved until adolescence and declined in adulthood; functional hand use was present at all ages despite stereotypies; and cognitive and communication abilities, although limited, did not deteriorate with age [17,50].

Frequencies according to GeneReviews [1].

Nervous system. Midline hand stereotypies (wringing, squeezing, clapping, tapping, mouthing, “washing” or rubbing the hands) are the most recognisable sign [17,30]. Gait, when acquired, is usually broad-based, dyspraxic or ataxic [17]. Abnormalities of tone develop, especially in the lower limbs, with dystonia, progressive spasticity and, in adulthood, parkinsonian signs [17,18]. Epilepsy affects 60–80% of patients and the electroencephalogram (EEG) frequently shows epileptiform discharges during sleep; epileptic seizures must be distinguished from non-epileptic episodes (breathing abnormalities, staring, tremor) [1,18]. Rett syndrome may be mistaken for dyskinetic cerebral palsy and is among the conditions to exclude in that context [51]. Secondary cerebral folate deficiency, with reduced cerebrospinal fluid 5-methyltetrahydrofolate levels that are less low than in primary folate receptor deficiency, has been described in Rett syndrome [52].

Respiration and autonomic nervous system. Episodes of hyperventilation and apnoea while awake, Valsalva breathing, hypoventilation and cyanosis occur, together with aerophagia and abdominal distension [17,18]. Rett syndrome appears in lists of genetic causes of hyperventilation attacks in children [53]. Peripheral vasomotor abnormalities manifest as small, cold hands and feet [30]. Autonomic dysfunction of respiratory and cardiac rhythm and seizures contribute to increased mortality [17]. Prolongation of the corrected QT interval (QTc) increases the risk of potentially fatal arrhythmias [1].

Gastrointestinal system and nutrition. Feeding difficulties, dysphagia with aspiration risk, gastro-oesophageal reflux, chronic constipation, aerophagia, drooling, delayed weight gain and linear growth; gallbladder disease and biliary dyskinesia are reported in adulthood [1,18,54].

Musculoskeletal system. Scoliosis or kyphosis (causing or worsening restrictive respiratory problems), osteopenia with fracture risk, contractures and hip dislocation [1,18,55]. In the Australian and international adult cohort, 86% had scoliosis and 40% of these had undergone surgery [54].

Sleep, behaviour and communication. Disturbed sleep pattern (night waking, daytime somnolence), inappropriate laughing or screaming episodes, anxiety, agitation and intense communication through eye gaze (“eye pointing”); pain sensitivity appears reduced [18,30].

Other associations mentioned in the Brazilian source. Restless legs syndrome, familial cholestasis, pulmonary aspiration, gastro-oesophageal reflux, constipation and osteopenia [18].

Natural history data compiled by the French protocol. The 2017 PNDS (French National Diagnosis and Care Protocol) collates frequencies from published series (mainly the Australian database, the Italian and Dutch cohorts and parent surveys), which describe patients followed in centres rather than the general population [12]. In gross motor function, 80% achieve unsupported sitting, 69% crawling and 62% standing with help; the proportion who walk ranges from 43% to 51.8% across series, depending on whether walking with minimal assistance is included, and motor scores for sitting, standing and walking decline after 19 years, probably related to scoliosis and bradykinesia [12]. Almost three quarters can touch, grasp, hold and release an object, but only 25% finger-feed, 19% hold a bottle or cup and fewer than 10% hold cutlery or transfer objects between hands [12]. After 30 years, 18% walk independently and 43% with support, 15% do not walk, 85% sit without help, 66% cannot perform the sit-to-stand transfer, 40% have no voluntary grasp and 28% of adult women are fed by gastrostomy, exclusively or as a supplement [12]. In communication, 82.8% make choices with their eyes, with a choice time of less than 8 seconds in more than half and no variation with age; in eye-tracking studies they fixate facial features for less time than controls (48% versus 72%), especially the mouth [12].

Epilepsy affects 70–90% of patients in the series collated by the PNDS, usually beginning after regression and after 3 years (median 4.7 years) and rarely after 20 years; three profiles are distinguished: seizures responsive to treatment (55–70%), active epilepsy with frequent seizures (16–45%) and absence of seizures (10–18%) [12]. Focal seizures, with or without secondary generalisation, occur in 94% and generalised seizures in 56%, and the combination of complex focal, tonic and tonic–clonic seizures in 80%; about 40% of episodes described as seizures are not confirmed on video-EEG, being tremors, jerks, falls, head rotations, pseudo-absences with unmotivated laughter or mydriasis, and breathing dysrhythmias, which leads to overestimation of epilepsy and overmedication [12]. After 20 years generalised seizures decrease and focal seizures increase, and epilepsy in adult women responds better to drugs than in children [12]. Hand stereotypies appear at a mean age of 25 months, more than 95% of patients have more than one and one third have five or more (hand-washing with bruxism in about 70%, hand-washing with hands in the mouth in 45%); patients do not look at their hands during the stereotypies, unlike autistic children, and the stereotypies become less complex after 10 years, evolving towards hypokinesia and extrapyramidal rigidity, earlier in those who never walked [12]. Awake bruxism affects 82%, myoclonus of the head and trunk about one third, and freezing occurs at gait initiation [12].

Abnormalities of respiratory control (hyperventilation alternating with irregular breathing or hypoventilation) occur in 65–93%, with the highest prevalence between 10 and 18 years: forced and apneustic breathing predominate between 5 and 10 years, Valsalva-type breathing after 18, and Biot-type breathing from 10 to 18 years is associated with non-epileptic pseudo-absences [12]. Sleep disturbances affect more than 80%, with night laughing in 77% and night crying in 49% of children under 7 years, nocturnal bruxism in 50% and night screaming in 28%; daytime sleepiness increases with age and there is a risk of central or obstructive apnoeas and alveolar hypoventilation [12]. The protocol reports QTc prolongation (>0.45 s) in 30–40%, with no identified risk factor, and considers it the presumed cause of some sudden deaths [12]. Series with systematic ECG give lower proportions and identify associated factors: in an Australian prospective cohort of 34 girls, QTc was prolonged in 9 (26%), unrelated to clinical severity [56]; in a North American retrospective review of 129 patients (349 ECGs, 2012–2018, threshold 460 ms), 12 (9.3%) had a prolonged QTc on the first ECG, associated with moderate or severe breathing abnormalities (66.7% versus 24.8%) and selective serotonin reuptake inhibitor use (41.7% versus 15.4%), and 26 developed prolongation during a median follow-up of 1 year and 7 months, with higher risk for the p.(Thr158Met) variant (hazard ratio 4.1; 95% CI 1.4–12.0) [57]. Prolongation may therefore arise between two ECGs 3 years apart, and abnormal breathing, SSRIs and the p.(Thr158Met) variant justify closer surveillance. In behaviour, daytime and night-time screaming occurs in 39–84%, awakenings with night laughing in 64–84%, self-injury in 28–73%, low mood in 66–77% (worsening after 25 years) and anxiety with inappropriate fear in 68–75%; autistic features persist after regression and are unrelated to neurological severity [12].

Gastrointestinal dysmotility is reported in 92% and chewing and swallowing difficulties in 81%; growth failure begins from 13 months, with peak onset between 7 and 12 years and no pubertal growth spurt, but mean BMI is normal, so that its deceleration is an indicator of undernutrition; about 25% have a gastrostomy, which improves undernutrition without normalising height or weight, whatever the age of placement [12]. On densitometry, 97% of children over 9 years have bone mineral density below −2 SD, mainly at the femur [12]. Scoliosis (Cobb angle >10°) affects 50% before 11 years and 75% before 13, with maximum thoracic curvature in 45%; the risk of severe scoliosis (>60° after 16 years) increases when the curve exceeds 25° before 10 years and when there is no independent walking, and is minimal in patients walking alone at 10 years with minimal or absent scoliosis; hip subluxation (femoral head migration ≥30%) reaches up to 48% [12]. About three quarters have non-physiological tooth wear from bruxism, and caries, gingivitis, delayed shedding of deciduous teeth and eruption of permanent teeth, and malocclusion are common [12]. In an Australian parent survey, 60% of patients had reduced pain sensitivity and 15% increased sensitivity, with a lower response to external causes and a greater one to internal causes (abdominal pain, headaches); the most frequent pain signs were facial expression (85%) and vocalisation (82%), and the most frequent origin was gastrointestinal (66%) [12]. In family health-status surveys, epilepsy was reported in 79.1% over the lifetime and in 51.6% in the last month, reflux in 60.4% and 35.1%, constipation or subocclusion in 56.0% and 41.7%, dental problems in 42.8% and 12.1%, skin problems in 40.6% and 29.7%, respiratory infections in 28.6% and 11%, and eye problems in 22% and 8.8% [12].

3.2. Atypical (variant) Rett syndrome

Atypical variants exhibit a broader spectrum than the classical form [1]. At the severe end, development is delayed from early infancy, with congenital hypotonia and infantile spasms; at the mild end, regression is less marked, intellectual disability is less severe and speech may be preserved [1]. The three recognised classical variants were the congenital variant, the preserved speech variant (described by Zappella in 1992) and the early-seizure variant [18,30,58]. Important groups of girls with atypical Rett, less frequently associated with MECP2 variants, are those with congenital onset, often with early epilepsy, and those with a mild course and developmental stagnation rather than marked regression [17]. Identification of the causes of the early-seizure variant (CDKL5) and congenital variant (FOXG1) led to their reclassification as separate entities (sections 3.5 and 3.6) [3,4].

In the 2017 French protocol, typical forms account for about three quarters of cases and atypical forms for about one quarter [12]. The early-seizure variant presents, in a girl (rarely in a boy), with clusters of clonic or tonic seizures before 5 months, progression to infantile spasms (West syndrome) before the first year, drug-resistant myoclonic epilepsy, severe delay and hand stereotypies; the congenital variant, in both sexes, with severe delay, congenital or early postnatal microcephaly from 4 months, dyskinesia, generalised mobile dystonia and buccolingual dyskinesias; the preserved speech variant is often recognised around 4 years during investigation of an autistic disorder, with some words or echolalic phrases, hand use sometimes preserved, frequent stereotypies, mild motor involvement and absence of microcephaly, growth failure, scoliosis, dysautonomia and epilepsy [12]. The French CDD protocol adds the classification into five atypical forms: with early-onset seizures (Hanefeld type), congenital (Rolando type, the most severe, with Rett signs in the first three months), forme fruste (less severe, with onset in early childhood and incomplete course), form with late childhood regression (normal head circumference and more gradual regression) and preserved speech variant (Zappella type, with recovery of some verbal and manual abilities) [14]. “Rett-like syndromes” is the term used for presentations with developmental delay, with or without regression, deceleration of head growth, hand stereotypies and eye pointing that do not fulfil the criteria [12].

Frequencies according to GeneReviews [1].

3.3. Other MECP2 phenotypes

Rarely in females, a pathogenic MECP2 variant manifests only as mild learning difficulties or autistic traits, probably owing to favourable X inactivation; without a regression phase or characteristic stereotypies, the course differs from classical and atypical forms; these women are usually identified following diagnosis in a first-degree relative [1]. The severe encephalopathy phenotype is rare in females [1]. The spectrum also includes girls previously clinically diagnosed with Angelman syndrome or autism; in a study of girls with unexplained intellectual disability, two variants were found among 63 girls investigated for Angelman with normal SNRPN methylation (~7%), one among 92 girls with negative fragile X testing (~1%) and none among those investigated for Prader–Willi [17].

In males, severe neonatal encephalopathy is characterised by microcephaly, a relentless course resembling a metabolic-degenerative disorder, abnormalities of tone, involuntary movements, severe seizures and breathing abnormalities, including central hypoventilation or respiratory failure [1]. When the variant is not lethal, severe syndromic or non-syndromic intellectual disability or PPM-X syndrome develops [1,45].

Frequencies according to GeneReviews, which brings together the Schüle series (encephalopathy), several PPM-X families and male ID series [1]. In PPM-X, the presentation includes moderate to severe ID, frequently progressive spasticity, extrapyramidal signs, episodic psychosis and macro-orchidism, with variable microcephaly; resting tremor, slowness of movement and ataxia, without seizures or microcephaly, and with normal magnetic resonance imaging (MRI), EEG, electromyography and conduction velocities [1].

3.4. MECP2 duplication syndrome

The syndrome is fully penetrant in males and more than 300 boys have been described, with a consistent presentation across series [2]. Growth at birth, including head circumference, is usually normal and remains normal in childhood according to GeneReviews; Smith's reports growth delay beginning prenatally, with normocephaly more common but microcephaly possible, and associates growth delay, microcephaly, malformations and more marked dysmorphism with larger Xq duplications [2,47].

Sources: GeneReviews and Smith's Recognizable Patterns [2,47].

In the first weeks, feeding difficulties arise owing to hypotonia, dysphagia, gastro-oesophageal reflux, poor weight gain and profuse drooling; nasogastric feeding and, later, fundoplication or permanent gastrostomy may be necessary [2]. Motor delay is severe; one-third never walk independently; in some children who had used words, speech was progressively lost in adolescence, and 80% of boys initially using words regressed and never regained speech [2,47]. In 65%, hypotonia gives way to spasticity in childhood, with contractures and frequent wheelchair dependence in adulthood [2]. Median age at seizure onset is six years; the most frequent types are atonic, tonic–clonic, tonic and atypical absence seizures; there is no specific electroclinical phenotype and 82% of boys with epilepsy have refractory seizures; seizure onset and severity frequently accompany neurological deterioration, with loss of speech, hand use or walking [2,59]. Recurrent respiratory infections, mainly pneumonias potentially requiring assisted ventilation, occur in 75% and may be fatal [2]. Smith's describes low serum IgA and IgM, raised IgG, poor responses to polysaccharide antigens and poor T-cell responses to Candida, and reports fewer infections with intravenous or subcutaneous immunoglobulin, although the underlying immune defect remains undetermined in most cases [47].

Dysmorphism is mild: brachycephaly, premature fontanelle closure or a prominent metopic suture, facial hypotonia, midface hypoplasia, hypertelorism, epicanthic folds, depressed nasal bridge, anteverted nares, small open mouth, thin tented upper lip, high palate with hypertrophic alveolar ridges and large, low-set, posteriorly rotated ears [2,47]. Also observed are mottled skin, urogenital abnormalities (bladder dysfunction, cryptorchidism, micropenis, hypospadias, hydrocele), strabismus or amblyopia and, occasionally, heart defects, pectus, hernias, scoliosis, pulmonary sequestration, small hands and feet, syndactyly, clinodactyly, clubfoot, deafness, hypothyroidism and eczema [2,47]. Neuroimaging may show corpus callosum hypoplasia, mild cerebral atrophy, ventriculomegaly, external hydrocephalus, non-specific white matter abnormalities and inferior cerebellar vermis hypoplasia [2,47]. Autistic traits include anxiety, hand stereotypies and reduced sensitivity to pain and temperature [2]. Intestinal pseudo-obstruction is one of the cardinal manifestations cited by the Oxford Desk Reference [45].

Heterozygous women. Most have extreme or complete skewing of X inactivation and are asymptomatic, but neuropsychiatric symptoms (depression, anxiety, compulsions, autistic traits) with normal cognition have been described [2,47]. Approximately 20 women with symptomatic interstitial Xq28 duplication have been described, half with a de novo duplication (frequently on the paternal allele) and half inherited from an apparently asymptomatic mother; the phenotype ranges from non-specific mild ID to a presentation resembling that in males, and severity does not necessarily correlate with the X-inactivation pattern in blood [2]. Short stature, developmental delay, facial dysmorphism and gonadal dysgenesis occasionally occur [47].

Data from the 2019 French protocol. The PNDS (French National Diagnosis and Care Protocol), whose frequencies refer to boys, states that the duplication is maternally inherited in more than 90% of cases and accounts for about 1% of X-linked ID [13]. Stereotypies (hands, upper limbs and sometimes head, with very frequent bruxism) occur in about 50%, usually appear at school age and may persist into adulthood, unlike those of typical Rett syndrome, which accompany the loss of purposeful hand use between the first and fourth years and diminish after 10 years [13]. Epilepsy affects about half of boys, with a median age at onset of 7 years and frequency increasing with age; seizures are mainly generalised tonic–clonic, but also tonic, myoclonic, atonic, absences, late spasms and complex focal; in boys with epilepsy the EEG is always abnormal (slow background activity with bilateral spike-waves and posterior theta rhythms), drug resistance is the rule and seizure onset is followed by regression (speech, hand use, walking) in about 40%, especially when refractory [13]. About half have apparently reduced pain sensitivity, according to parents [13].

The protocol describes a facies with prominent forehead, midface hypoplasia, large ears, deep-set eyes, thin and prominent nasal bridge, prominent chin and thick lower lip; small hands and feet with tapering fingers and sometimes camptodactyly; livedo of the limbs in childhood, which tends to disappear in adolescence; moist extremities, sometimes erythematous and sometimes pale; dense hair with a sparser area over the lateral frontal regions and sparse eyebrows; prominent upper central incisors in half and persistence of deciduous teeth in the great majority, often requiring several extractions [13]. Gastro-oesophageal reflux affects 50%, chronic constipation 80% and abdominal bloating 40%, with subocclusive episodes; feeding difficulties in the first weeks tend to ease later [13]. Recurrent infections (pneumonia, acute otitis media, sinusitis and, less often, meningitis and urinary tract infections) affect more than 75%; susceptibility is associated, in variable combination, with IgA and IgG2 deficiency, low antipneumococcal antibody titres and an exaggerated acute inflammatory response, and these infections, together with neurological deterioration and epilepsy, account for death before 25 years in more than 25% of boys, according to the protocol [13]. One third have mild to moderate hearing loss, mainly conductive from recurrent otitis, but sometimes mixed; hypermetropia occurs in 50% and strabismus, usually divergent, in 75%; less frequently there is inguinal hernia, cryptorchidism, micropenis, hypospadias, bladder dysfunction, postnatal growth retardation, precocious puberty and pulmonary hypertension [13]. In women, duplications resulting from X–autosome translocation may cause a severe picture similar to that in males; the protocol applies to boys and to the rare girls with this phenotype, and not to carriers with isolated psychiatric disorder [13].

3.5. CDKL5 deficiency disorder (CDD)

CDD is a developmental and epileptic encephalopathy (DEE) with severe, early-onset and frequently intractable epilepsy, associated with motor, cognitive, visual and autonomic abnormalities and movement disorders (chorea, dystonia, hand and lower-limb stereotypies) [3]. Approximately 500 people have been identified [3]. Although the female:male ratio is approximately 4:1, severity in heterozygous females and hemizygous boys may be equivalent; severity depends on variant type and position, X inactivation and postzygotic mosaicism, which may be associated with mild presentations [3]. Cardiac involvement is non-specific [3].

Frequencies according to GeneReviews, based on the International CDKL5 Disorder Database and the international CDKL5 clinical research network [3].

Epilepsy. It typically begins in the first two months of life (up to 12 months), with multiple daily seizures [3,60]. Epileptic spasms are the first seizure type in almost 25% of patients and, among these, half occur without hypsarrhythmia; subsequent types include tonic, focal, myoclonic, generalised tonic–clonic and mixed seizures with spasm, tonic and hypermotor components [3]. Epilepsy is refractory throughout life, but up to 40% have a temporary improvement (“honeymoon period”) between one and two years of age [3]. The EEG may initially be normal and evolves towards abnormal background activity, sometimes with a Lennox–Gastaut pattern [3]. Seizures begin much earlier than in Angelman syndrome [61]. In the Oxford Desk Reference, CDKL5 appears as a cause of X-linked infantile spasms in girls due to de novo variants [62].

Development. Approximately 60% acquire sitting, approximately 20% walk independently, 40–70% cannot grasp and hold objects and approximately 20% have spoken language; most use simple forms of non-verbal communication [3]. Hypotonia is marked; eye contact is frequently poor and autonomic manifestations are less marked than in Rett syndrome; head circumference may be normal and a smaller head circumference is associated with greater severity; hand stereotypies are usually present [3,17,63].

Vision. Cerebral visual impairment manifests as horizontal and rotatory nystagmus, disconjugate eye movements, esotropia or exotropia, poor fixation and tracking and an abnormal response to bright light (for example, absence of blinking), and may improve with age [3].

Other systems. Sleep is not maintained, and sleepless nights alternate with excessive somnolence throughout life [3]. Constipation and gastro-oesophageal reflux persist; one-third require gastrostomy and the remainder have feeding difficulties with aspiration risk [3]. Scoliosis and hip and knee subluxation or dislocation, aspiration pneumonia and, occasionally, autistic behaviours occur [3]. MRI is normal in the first year in 64% (14/22) and subsequently shows progressive cortical and cerebellar atrophy, possibly more evident in males [3]. Families rank seizures as their main concern, followed by communication, sleep and vision [3].

Data from the 2021 French protocol. The CDD PNDS places the median age at seizure onset at 5–6 weeks [14]. At disease onset, tonic seizures predominate, often in clusters several times a day (32%), together with epileptic spasms (23%) and generalised tonic–clonic seizures (22%), and less often clonic (9%) and myoclonic (7%) seizures; over the lifetime, spasms are the most frequent type (82%), followed by tonic (64%), myoclonic (39%), generalised tonic–clonic (34%), clonic (11%) and atonic (9%) seizures and absences (2%) [14]. Sequences of tonic seizures alternating with spasms, described as characteristic (spasm–tonic–hypermotor sequences), occur in 25–60%, and focal seizures or asymmetric spasms in 30% [14]. Seizure-free periods (honeymoon), mainly in the first two years but also later, lasted 1–3 months in 9%, 3–6 months in 12% and 6–12 months in 11% of the series; a three-stage course (early epilepsy still drug-responsive, epileptic encephalopathy with spasms, myoclonic and multifocal epilepsy) has been described in some patients [14]. The EEG shows few abnormalities in the first three months, despite daily seizures, evolves from 6 months towards hypsarrhythmia and, after 2 years, towards global slowing with posterior predominance and pseudoperiodic epileptiform activity, generalised or focal; a neonatal burst-suppression pattern is rare [14].

According to the same protocol, head circumference is usually normal at birth and microcephaly is seen in only 10%; dysmorphism is subtle (deep-set eyes, high and broad forehead, prominent lips, marked philtrum, tapering fingers) and psychomotor regression is rare, except with worsening seizures [14]. Boys are generally more severely affected, and mild male forms are associated with somatic mosaicism [14]. Among girls, 20–25% walk independently; functional hand use is present in 60% of girls and 12% of boys, with raking grasp in 50% and thumb–index pincer grasp in 10–15%, and absence of grasp between 4 and 6 months is common [14]. Stereotypies (80%) are mainly self-stimulatory, such as repetitive leg crossing, intermittent and less intrusive than in Rett syndrome; spasticity is rare and hypotonia almost constant [14]. Fewer than 50% acquire babbling before 6 years and 15% use single words at 7 years; 25% of girls communicate with pictograms and 7.5% speak in simple sentences (no boys), and the use of eye-tracking devices is limited by cerebral visual impairment, present in more than 75% (poor visual attention, poor fixation and tracking, rotatory nystagmus, absent optokinetic nystagmus response and normal fundus) [14]. Sleep disturbances affect more than 80% (night waking in 60%, peaking between 5 and 10 years), and gastrointestinal disturbances more than 85% (constipation 70%, reflux 65%); in the international database, 79% are fed orally, 21% enterally and only 5% eat or drink independently [14].

Genotype–phenotype. Nonsense variants appear equally severe throughout the protein, although terminal-region truncating variants may be less severe; correlations are still emerging [3].

3.6. FOXG1 syndrome

FOXG1 syndrome is characterised by severe global delay beginning in the first months, moderate to profound intellectual disability too severe for standardised testing, absent speech in most, a hyperkinetic/dyskinetic movement disorder, hypotonia, congenital or postnatal microcephaly, postnatal growth deficiency, neurobehavioural manifestations, feeding difficulties, reflux, strabismus, epilepsy and spasticity [4,29,64]. More than 150 people with an intragenic FOXG1 variant or deletion have been identified [4].

Frequencies according to GeneReviews and the Mitter (83 patients) and Brimble (122 patients, registry) cohorts [4,64]. BMI: body mass index; SD: standard deviations.

Only approximately 50% acquire unsupported sitting (mean age 28 months) and 15% unsupported walking (mean age 53 months); among 83 patients, 21% had some verbal expression, with first words at a mean of 46 months and a mean of 19 words [4,64]. Mean epilepsy onset is at 25 months (3 months to 14 years), rarely after six years, with infantile spasms, focal, complex focal, generalised tonic, atonic and myoclonic seizures; three unrelated patients with a missense variant at amino acid 187 developed Lennox–Gastaut syndrome [4,64]. In the Oxford Desk Reference, epilepsy appears after three months and mainly after the first year, and dystonic and choreiform movements from the second year [17,65]. Among children aged three years or older, 19% had an autism spectrum disorder diagnosis, a diagnosis to use cautiously given the severity of ID [4]. Birth length and weight are normal in 85% and 93%, but at follow-up 48% have short stature and 34% low weight [4]. In intragenic variants there is no specific dysmorphism; the Oxford Desk Reference mentions a bulbous nasal tip and thick lips, findings more characteristic of contiguous deletions [4,17].

Neuroimaging. This is the most distinctive marker: corpus callosum abnormalities, especially thread-like thinning of the rostrum, a simplified gyral pattern (mainly frontal) and fornix hyperplasia; the combination of all three occurs in approximately 50% and is highly characteristic, possibly pathognomonic; enlargement of the internal CSF spaces and hypoplasia of the basal ganglia and frontal lobes are also observed; imaging severity correlates with clinical severity and MRI may rarely be normal [4,49]. Fornix thickening was described only in 2019 and frequently goes unrecognised [4]. Figure 1 of Pringsheim and colleagues shows the spectrum of structural abnormalities (gyration, corpus callosum and fornices) in patients with FOXG1 syndrome: https://pmc.ncbi.nlm.nih.gov/articles/PMC6469254/figure/acn3735-fig-0001/ [49]. Corpus callosum agenesis or hypoplasia with a movement disorder is a diagnostic clue [66].

Data from the 2018 French protocol. The PNDS (French National Diagnosis and Care Protocol) collates frequencies from published series: mainly axial hypotonia in 100%, severe postnatal microcephaly (−4 to −6 SD) from 3 months in 65–84%, dyskinetic movement disorder with generalised hyperkinesia and buccolingual involvement in 72–84%, hand stereotypies in 73–90%, early esotropia or exotropia in 52–77% (strabismus in 79–91% in the series describing it, mainly permanent esotropia, in 90% of these), crying or screaming in 63–66%, sleep disturbances in 64–76% and epilepsy in 68–79% [15]. Dysgenesis of the corpus callosum (from complete agenesis to frontal hypogenesis of the rostrum) was observed in 95.6%, gyral abnormalities (from frontal pachygyria to moderate simplification) in 84% and delayed myelination, which corrects after 3 years, in 65% [15]. Epilepsy begins at a mean of 25 months (from 2 days to 12 years; first quartile before 8 months, median 18 months, last quartile after 29 months), with generalised tonic–clonic (60%), focal (31.5%), spasms (20%), atonic and myoclonic seizures; 14.3% had at least one episode of status epilepticus and 48.6% progress to drug resistance [15]. Dyskinesias appear in the first year, worsen over the following months and then stabilise; they combine dystonia, chorea and athetosis, with rhythmic tongue protrusion and mouth opening and closing, and no status dystonicus has been reported; hand stereotypies differ from those of Rett syndrome in being intermittent, not necessarily bimanual or midline, without hand clapping, and bruxism affects about 50% [15].

Sitting is achieved by 40–45% (usually with help) and walking by 6.7–15% (mean age 53 months), and motor regression occurs in 18%; 29.5% have only gross manipulation and 14–40% can transfer objects or bring them to the mouth [15]. Fewer than 20% acquire two-syllable words; social interactions are rated as good in 51–79% and eye contact as poor in 52–73%, without the intentional eye pointing of Rett syndrome; in a study of 8 children, visual acuity was adequate, but visual engagement was rare and attention to distant stimuli limited [15]. Unmotivated laughter occurs in 44–46%, feeding difficulties in 80–88%, reflux in 65–84% and constipation in 75–84%; height is below −2 SD in 43–48% and BMI below −2 SD in 30–34%; about 50% have a gastrostomy; and scoliosis affects 40–55% [15]. The median age at follow-up in the series is 105 months (14 to 384 months); fewer than five adults had been recorded in France, without regression, and the only published adult case describes an akinetic-rigid syndrome with persistent dyskinesias and stereotypies [15].

“FOXG1 plus” syndrome and 14q12 duplication. Large 14q12q13 deletions (contiguous gene syndrome) cause a more severe neurological picture with characteristic facial dysmorphism: round and broad face, flat forehead, flat midface, epicanthus, depressed nasal root with anteverted nares and large ears, and complete agenesis of the corpus callosum; variability depends on the extent of the deletion and its content (PRKD1, NOVA1, NKX2-1, PAX9, C14orf23), and the diagnosis has rarely been made prenatally on the basis of callosal agenesis or hypogenesis [15]. Duplications of FOXG1 or of 14q12 cause a distinct encephalopathy: normocephaly, absence of movement disorder and of corpus callosum anomalies, severe ID with minor motor involvement and epileptic encephalopathy with onset at a mean of 7.4 months, mainly West syndrome, with response of spasms to corticosteroids and a more favourable course than in FOXG1 syndrome [15].

Genotype–phenotype. Truncating variants and intragenic deletions cause more severe phenotypes than missense variants; the most severe are associated with frameshift or nonsense variants in the N-terminal domain and in the forkhead domain outside conserved site 1, and the mildest with missense variants in conserved site 1; simplified gyration is more frequent with N-terminal truncating variants [4,49,64]. Whole-FOXG1 duplications cause milder developmental delay, earlier-onset epilepsy (frequently infantile spasms responding well to hormonal treatment), normal head circumference and neuroimaging; compared with these, deletions and intragenic variants have later epilepsy diagnosis, more antiseizure medications, worse walking and worse hand use, with language and social skills equally affected [4]. FOXG1 duplications also appear among rare causes of infantile spasms [62].

4. Clinical Recognition and Red Flags

The earliest red flag for Rett syndrome is deceleration of head circumference growth in a girl with apparently normal early development; the 2010 criteria indicate that the diagnosis should be considered whenever this deceleration is observed [17,30]. In a girl with developmental regression, especially between 6 months and 2 years, Rett syndrome is the first diagnosis to consider; in a boy with regression, X-linked conditions such as X-linked adrenoleukodystrophy and Pelizaeus–Merzbacher disease are considered first [67]. On examination, deceleration of head growth (also present in Cockayne syndrome), hand-wringing stereotypies and scoliosis (also in Friedreich ataxia) are clues to Rett [67]. In girls with autism and a history of normal early development followed by regression, MECP2 analysis is recommended [68]. Rett syndrome is also among diagnoses suggested by abnormal movements, behaviour or gait in the investigation of epilepsy with developmental delay [69].

History-taking should record the perinatal history, head circumference at birth, developmental milestones (usually normal in the first 6–18 months), age at first concerns, loss of skills (babbling or words and hand use), a transient period of agitation with social withdrawal, seizures, altered sleep–wake cycle and inappropriate laughing or crying episodes [17]. Examination assesses eye contact, hand stereotypies (wringing, clapping, tapping, mouthing, flapping), abnormal periodic ventilation (hyperventilation and apnoea, Valsalva breathing, hypoventilation) and cyanosis, broad-based dyspraxic or ataxic gait, head circumference, tone and lower-limb tendon reflexes, kyphosis or scoliosis and small, cold hands and feet [17].

The table integrates signs from the Oxford Desk Reference and the GeneReviews chapters [1–4,17]. In male neonatal encephalopathy with intractable seizures, the Oxford Desk Reference recommends considering variants in ARX, NEMO and MECP2 [70]. For Xq28 duplications, the Oxford Desk Reference emphasises male hypotonia and epilepsy, pseudo-obstruction and premature closure of the fontanelles or metopic suture [48,69].

In the series collated by the French protocol, the median age at diagnosis was 2.7 years (range 2.0–4.1) in classical Rett syndrome and 3.8 years (2.3–6.9) in atypical forms [12]. Warning signs change with age: between 2 and 4 years, the combination of developmental delay, acquisition followed by loss of hand use and babbling, hand stereotypies and autistic features with loss of contact and, after 3 years, the appearance of eye pointing; from 4–6 years, the contrast between eye pointing and absence of language, breathing abnormalities while awake, growth failure with small hands and feet, and kyphosis or scoliosis; in adolescent and adult women, multiple disability in a woman of short stature with stereotypies, breathing abnormalities, parkinsonian rigidity and early trophic changes of the skin and nails, with deterioration of mood and less interest in the surroundings, especially after 25 years [12]. In MECP2 duplication, the protocol highlights, in the first year, the variable combination of hypotonia, delay, feeding difficulties with reflux, marked constipation and recurrent respiratory infections; with the widespread use of microarray and exome analysis, the duplication is increasingly identified without prior clinical suspicion, and diagnosis tends to be earlier [13]. In CDD, the warning signs in infants are epilepsy before 3 months or spasms, delay preceding the seizures with hypotonia, poor head control and poor eye contact, and absent or delayed grasp before 6 months; in children, early drug-resistant epilepsy, often with hypermotor seizures, and severe delay without regression [14]. In FOXG1 syndrome, the signs are delay with axial hypotonia, microcephaly from 3 months, absence of visual tracking with strabismus or nystagmus, dyskinesias and stereotypies, unmotivated crying and hypogenesis or agenesis of the corpus callosum; in older children, complex dyskinesias with mild epilepsy; and, in adolescents or adults, multiple disability with marked microcephaly, absence of eye pointing, dystonia, athetosis and parkinsonian rigidity [15].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. The 2010 clinical criteria for Rett syndrome

Rett syndrome remains a clinical diagnosis; the revised 2010 criteria require a period of regression followed by recovery or stabilisation for both typical and atypical forms [17,30]. A pathogenic MECP2 variant is not, by itself, sufficient for a Rett syndrome diagnosis, and absence of a variant does not exclude it [1,30].

Criteria of Neul and colleagues (RettSearch, 2010), reproduced in the Oxford Desk Reference and GeneReviews [1,17,30]. Language loss is based on the best verbal skill acquired, so loss of babbling counts as language loss [30]. Because MECP2 variants are now identified before any regression, a child younger than three years without skill loss but with a suggestive presentation receives a “possible” Rett diagnosis and is reassessed every 6–12 months; if regression occurs, the diagnosis becomes definitive, and if there is no regression by five years the Rett syndrome diagnosis should be questioned [17,30]. According to GeneReviews, regression occurs between the first and fourth years and recovery or stabilisation between 2 and 10 years (mean 5 years) [1]. The Brazilian source briefly lists inclusion criteria (apparently normal prenatal and perinatal development, normal head circumference at birth, normal development in the first 6 months, hand stereotypies, gait apraxia) and supportive criteria (hyperventilation, apnoeas, seizures, scoliosis, growth retardation, spasticity, dystonia, vasomotor disturbances, sleep EEG abnormalities, bruxism when awake, disturbed sleep, chronic constipation and abdominal distension due to aerophagia) [18].

The 2017 French protocol reproduces the 2010 criteria and specifies three points of application: in a child under 5 years who has had regression and more than two main criteria but does not meet 5 of the 11 supportive criteria, a diagnosis of “probable” atypical Rett is proposed, reassessed every 6–12 months, because supportive criteria are age-dependent and become more evident in older girls; a supportive criterion present at any point in the history counts towards the diagnosis; and delay or hypotonia in the first 6 months, common in Rett syndrome, are not exclusion criteria, which require history, neurological and ophthalmological examination and brain MRI [12]. Deceleration of head growth was removed from the required criteria because it is not constant, but it remains a sign that should prompt consideration of the diagnosis; the atypical forms have molecular markers in the three main variants (MECP2 in preserved speech, CDKL5 in early seizures, FOXG1 in the congenital form), although a large proportion remain without an identified molecular cause [12].

5.2. Molecular testing for MECP2 disorders

The molecular diagnosis is established in a girl with a suggestive presentation and a heterozygous pathogenic or likely pathogenic MECP2 variant, or in a boy with a hemizygous variant; a variant of uncertain significance neither establishes nor excludes the diagnosis [1]. When the presentation is suggestive, gene sequencing is used, followed, if negative, by intragenic deletion and duplication analysis (for example, MLPA, multiplex ligation-dependent probe amplification), or a multigene panel (Rett/Angelman or infantile epilepsy) including deletion/duplication analysis; when the phenotype is non-specific (ID, neonatal encephalopathy), exome or genome sequencing is preferred, with an exome array if the exome is non-diagnostic [1]. Sequencing detects 90–95% of pathogenic variants and deletion/duplication analysis 5–10% [1]. The Oxford Desk Reference gives a detection rate of approximately 95% with sequencing and MLPA in the classical form, whereas its developmental regression chapter gives approximately 80%, probably reflecting studies predating systematic deletion analysis; the Brazilian source reports 95–97% [17,18,67]. The same book recommends considering genomic microarray and next-generation panels including MECP2 and genes causing Rett-like presentations, or exome/genome; in early epilepsy, investigate CDKL5 and other epileptic encephalopathy genes; in congenital onset without epilepsy, investigate FOXG1 [17]. The Brazilian source systematises additional investigations (including follow-up EEG showing epileptiform discharges during sleep) and lists other genes associated with Rett-like presentations (CDKL5, FOXG1, HCN1, GRIN2B, SLC6A1, SCN1A) [18].

5.3. MECP2 duplication syndrome

The diagnosis is established by identification of a duplication of the entire MECP2 [2]. The first-line test is chromosomal microarray (CMA), whose current designs cover Xq28 and detect 100% of duplications in affected boys; single-gene sequencing is rarely useful and is not recommended; G-banded karyotyping detects only Xq28 duplications larger than about 8 Mb, so an affected boy may have a normal karyotype [2]. Because this is a copy-number variation, it is diagnosed only by quantitative methods (CMA, MLPA, quantitative PCR or copy-number variant calling from genome data) [2]. Parental karyotypes and fluorescence in situ hybridisation (FISH) are used to exclude predisposing rearrangements [47]. The likelihood of detecting the duplication is higher when there is a clear X-linked inheritance pattern [2]. The French protocol designates microarray (available in all French university hospitals) as the confirmatory test, considers targeted testing by MLPA or quantitative PCR obsolete, recommends systematically offering testing of the mother to distinguish a de novo from an inherited duplication, and recommends referral to a clinical geneticist when the test is negative and the picture is suggestive [13].

5.4. CDKL5 deficiency disorder

The minimum clinical criteria proposed by Olson and colleagues are motor and cognitive developmental delay and epilepsy with onset in the first year of life; the diagnosis is established with a pathogenic or likely pathogenic heterozygous (girl) or hemizygous (boy) variant in CDKL5 [3,60,71]. Sequencing detects 84% and deletion/duplication analysis 16% of variants [3]. The preferred approach is an epilepsy panel or exome/genome sequencing; single-gene testing is not recommended [3]. The laboratory should analyse transcript NM_001323289, have sufficient depth to detect mosaicism and, when suspicion is strong and panel or exome are negative, genome sequencing should be considered; maternal testing helps classify missense variants of uncertain significance outside the kinase domain [3]. In childhood epilepsy panels, diagnostic yield is higher when seizures begin before two months, about 40% [62]. EEG, MRI and visual assessment are supportive, not diagnostic; a normal EEG or one without hypsarrhythmia does not exclude CDD [3]. The 2021 French protocol includes in the confirmation of the diagnosis of developmental and epileptic encephalopathy, by a paediatric neurologist, brain MRI with spectroscopy (usually normal in CDD) to exclude malformations or signal changes, and a metabolic work-up directed at treatable causes, with serum pipecolic acid and α-aminoadipic semialdehyde (α-AASA) for pyridoxine-dependent epilepsy, amino acid chromatography and measurement of neurotransmitters in cerebrospinal fluid; genetic testing (monogenic epilepsy panel, exome or genome, with microarray or panel for large deletions) can be requested in parallel, and targeted sequencing of CDKL5 alone is no longer performed in France [14]. It also recommends video-EEG from the first symptoms, ideally extended to 24 hours to record the different manifestations [14].

5.5. FOXG1 syndrome

The diagnosis is established in a proband with a characteristic clinical picture and/or neuroimaging and a pathogenic heterozygous FOXG1 variant [4]. Sequencing detects more than 95% and deletion/duplication analysis fewer than 5% of intragenic alterations; exome sequencing is the first option, with a yield similar to that of an ID panel (some ID panels do not include FOXG1); single-gene sequencing is not recommended [4]. The 14q12 deletion is often identified by microarray, which the Oxford Desk Reference includes in the investigation of children with dystonia [17,65]. The 2018 French protocol draws attention to the frequently insufficient coverage of FOXG1 in next-generation sequencing analyses, owing to the GC richness of the gene, so the molecular biologist should specifically review this region when the picture is suggestive; deletions removing cis-regulatory elements at a distance from the gene, the 14q12 deletions of “FOXG1 plus” syndrome and 14q12 duplications are identified by microarray (or by next-generation sequencing), and karyotyping has exceptionally shown a ring chromosome 14 or a translocation [15].

5.6. Integrated algorithm

Algorithm constructed from GeneReviews and Oxford Desk Reference recommendations [1–4,17].

5.7. Non-molecular assessment investigations

No biochemical or functional investigation confirms an MECP2 disorder [1]. Following diagnosis, disease burden is assessed with electrocardiography (QTc), EEG (with video if necessary), brain MRI, overnight sleep studies analysing respiratory regularity and non-invasive gas exchange assessment, portable polygraph screening for apnoea and hypopnoea, bone densitometry, orthopaedic and rehabilitation medicine assessment (scoliosis), gastroenterological and nutritional assessment (aspiration risk), ophthalmological and audiological assessment, and neuropsychiatric assessment from 12 months [1].

The French Rett syndrome protocol recommends an electrocardiogram at diagnosis in all patients and, if the QTc is prolonged, 24-hour Holter monitoring to look for tachyarrhythmias and referral to cardiology [12]. To measure severity, the same document proposes the Rett syndrome gross motor scale (Rett Syndrome Gross Motor Scale, 15 items scored from 0 to 3 according to the level of assistance, total 0 to 45, with subscales for sitting, for standing and walking and for more demanding tasks), the clinical severity scale (CSS, 13 domains, total 0 to 58), the clinical global impression of severity (CGI-S) adapted to the CSS domains, the motor-behavioural scale (37 items scored from 0 to 4, total 0 to 148, lengthy and not systematically validated) and the RSBQ behavioural questionnaire checklist [12]. No motor or behavioural scales have been developed specifically for CDD or for FOXG1 syndrome [14,15].

Table adapted from the assessment-at-diagnosis table of the MECP2 duplication PNDS (French National Diagnosis and Care Protocol) [13]. In CDD, disclosure of the diagnosis presupposes that MRI, EEG and ophthalmological assessment have already been performed [14].

5.8. Limits of genetic testing and report content

Coverage differs for each condition. In MECP2 disorders, sequencing does not detect deletions of one or more exons or large deletions, which require MLPA or another quantitative method, and variants in exon 1, exclusive to the e1 isoform, are rare but pathogenic, so analysis must include this exon [1]; short-read exome and genome sequencing detect point variants and may detect deletions and duplications through read depth, but with lower sensitivity than targeted analysis, so a negative exome does not exclude an intragenic deletion [1, 4]. In MECP2 duplication, only quantitative methods are diagnostic and sequencing is unhelpful; microarray does not identify the location of the duplication, so karyotyping and FISH are necessary to exclude a translocation or insertion [2,47]. In CDD, laboratories must analyse the brain transcript, provide sufficient depth for mosaicism and consider the genome for intronic and 5′ untranslated region variants [3]. In FOXG1 syndrome, most variants lie in the coding region of the single exon and are detectable by exome, but some intellectual disability panels do not include the gene [4]. Somatic mosaicism, described in boys with classical Rett syndrome, and parental germline mosaicism, which explains recurrences despite negative parental leukocyte testing, may not be detected by conventional blood sequencing [1]. A negative test does not exclude the clinical diagnosis of Rett syndrome, which remains based on the 2010 criteria [1,30].

The report should state the gene, reference transcript with version, HGVS nomenclature at coding DNA and protein level (or coordinates and gene content for CNVs), zygosity (heterozygosity, hemizygosity or mosaicism, with allele fraction), ACMG/AMP classification with the criteria applied and technical limitations; MECP2, CDKL5 and FOXG1 variants are interpreted according to ClinGen expert panel specifications, and CNVs according to the joint ACMG/ClinGen standard [1,72,73]. The MANE Select transcript is NM_001110792.2 for MECP2 (e1 isoform), with NM_004992.4 (e2 isoform) as MANE Plus Clinical; NM_001323289.2 for CDKL5; and NM_005249.5 for FOXG1 [74]. As almost all MECP2 literature uses e2 isoform numbering, the report should give both notations (section 2.1): p.(Arg168Ter) in the literature corresponds to NM_001110792.2:c.538C>T, p.(Arg180Ter) in ClinVar [42]. In CDKL5, historical transcript numbering for NM_003159 and NM_001037343 coincides with MANE up to nucleotide c.2713 and diverges in the terminal region, where variants classified as non-coding in older transcripts may be coding and pathogenic in the brain transcript [3]; for example, NM_001323289.2:c.2635_2636del, p.(Leu879fs), is recorded as pathogenic [42]. A variant of uncertain significance does not become pathogenic through treatment response or partial segregation; parental testing (de novo variant), X-inactivation analysis and expression studies may contribute to reclassification but should be described as additional investigation, and the molecular result does not replace the 2010 clinical criteria [1,30].

6. Differential Diagnosis

Table compiled from the Oxford Desk Reference, the Brazilian source, Saudubray, the GeneReviews chapters and the French FOXG1 syndrome protocol [1,3,4,15,17,18,53,61,62,67,75,76]. ERG: electroretinogram.

The French protocols organise the differential diagnosis by presenting phenotype [12,14,15]. In typical Rett, they mainly consider Angelman syndrome, Pitt-Hopkins syndrome (with voluntary grasp often preserved, macrostomia with widely spaced teeth, broad and shallow palate, thick lips, deep-set eyes, wide nares and thick helix) and autism spectrum disorders with transient regression; in the congenital form, hyperkinetic encephalopathies, microcephalies with simplified gyral pattern, STXBP1 encephalopathies and neurotransmitter disorders; in the early-seizure form, monogenic, malformative (lissencephaly) and metabolic epileptic encephalopathies responsive to pyridoxine or folinic acid [12]. In the differential diagnosis of CDD, the 2021 protocol distinguishes de novo variants of SCN2A (gain of function with epilepsy before 3 months and loss of function with later epilepsy and autism), KCNQ2 (neonatal epilepsy with asymmetric tonic seizures in clusters and discontinuous or burst-suppression EEG, spontaneous cessation of seizures in 50% and spasms in the first year in about 25%), STXBP1 (neonatal or infantile epilepsy with normal head circumference), SCN8A (prolonged clonic seizures before 3 months in half) and KCNT1 (migrating focal seizures between 1 and 3 months), the recessive forms due to TBC1D24, SLC25A22 and SLC13A5, and the X-linked forms due to PIGA and ARX, recommending high-throughput sequencing of all DEE genes when the picture is compatible [14]. In FOXG1 syndrome, the same reasoning separates the syndromes with postnatal microcephaly (MECP2 Rett, CDD, Angelman, CASK, Christianson, QARS1, KCNB1, IQSEC2, MEIS2, WDR45) from the dyskinetic epileptic encephalopathies (Pitt-Hopkins, STXBP1, GNAO1, GRIN1, FRRS1L, TBC1D24, GRIN2A and, more rarely, ARX, ATP1A3, SCN2A, SETD5, ALG13, TBL1XR1, ADCY5, PDE10A, PDE2A, KCNQ2, KMT2B, GRIN2B, UNC13A and CDKL5); compared with MECP2 Rett syndrome, absence of walking, hyperkinetic dyskinesia, more severe and earlier microcephaly and callosal dysgenesis point to FOXG1 [15].

The distinction between CDD and classical Rett syndrome is clinically important: typical Rett stereotypies (wringing, tapping, mouthing, evolving over time) are less distractible than those of CDD, and very early seizures and cerebral visual impairment are unusual in classical Rett [3,32]. In FOXG1 syndrome, the differential with CDD rests on the predominance of refractory infantile-onset epilepsy and progressive atrophy (without malformations) in CDD; with Rett syndrome, on normal development in the first 6–18 months, regression, absence of dyskinesia and normal neuroimaging in Rett; with Angelman syndrome, on its happy demeanour, ataxia and characteristic EEG [4]. Note that the MECP2 disorders GeneReviews still describes FOXG1 syndrome as having a short period of normal development before regression, whereas the specific 2024 GeneReviews indicates delay from the first months and rare regression (motor loss in 20%); the more recent description takes precedence [1,4]. In infantile-onset dystonia, the Oxford Desk Reference includes “congenital Rett syndrome” due to FOXG1, emphasising that the locus is autosomal and affects both sexes [65]. In the differential diagnosis of MECP2 duplication, as the phenotype is insufficiently distinctive, all intellectual disability without other specific findings should be considered, including int22h1/int22h2-mediated Xq28 duplication and the OMIM phenotypic series for syndromic and non-syndromic X-linked ID [2]. Microcephaly and spastic paraplegia are among the phenotypic clues to X-linked ID in which MECP2 appears alongside ATRX, PQBP1, SLC16A2 and KDM5C [45].

7. Treatment and Risk Management Strategies

7.1. General principles

Treatment of all conditions in the spectrum is individualised, multidisciplinary and focused on optimising abilities and quality of life, with a paediatrician or internist, neurologist or epileptologist, dietitian, gastroenterologist, rehabilitation physician and physiotherapist, occupational therapist, speech and language therapist, music therapist, dentist, orthopaedic surgeon, respiratory physician, cardiologist and psychosocial support for the family [1,71,77]. The consensus guidelines for the management of Rett syndrome across the lifespan, published in 2020 by Fu and colleagues, and the international consensus recommendations for CDD, published in 2022 by Amin and colleagues, are the core references [71,77]. The CDD recommendations table, with suggested timing for each assessment, is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC9251467/table/T1/ [71]. GeneReviews states that there are no published clinical practice guidelines for FOXG1 syndrome [4]; there is, however, the 2018 French national protocol, an expert consensus that also covers “FOXG1 plus” syndrome and 14q12 duplication [15]. The Oxford Desk Reference summarises the management of Rett syndrome as symptomatic and supportive, focusing on nutrition, seizure control, physiotherapy to maintain mobility and prevent scoliosis, breathing and communication, increasingly with eye-tracking technology; non-invasive ventilatory support, including at night, may help control the breathing dysrhythmia, without validation in trials [17].

In France, the Haute Autorité de Santé has published PNDS (French National Diagnosis and Care Protocols) for the four conditions: Rett and related syndromes (2017), FOXG1 and “FOXG1 plus” syndrome (2018), MECP2 duplication (2020) and CDD (2021) [12–15]. They are expert consensus documents from the reference centres of the DéfiScience and AnDDI-Rares networks, developed using the 2012 HAS method based on literature review, without formal grading of evidence, and serve as a reference for the attending physician for the care protocol and the application for exemption from co-payment [12,14]. All predate the European authorisation of trofinetide, and the CDD protocol describes ganaxolone only as a drug in a phase 3 trial [14]. They also point out that several drugs used in these conditions are used outside their marketing authorisation, a situation that, in France, requires informing the patient or legal representative, stating this on the prescription and justifying the prescription in the medical record [12,15].

7.2. Trofinetide in Rett syndrome

Trofinetide is a synthetic analogue of the N-terminal tripeptide of insulin-like growth factor 1 (IGF-1, glycine-proline-glutamate); the precise molecular mechanism of its effect on neurobehavioural symptoms is unknown [37]. Approval was based on the phase 3 LAVENDER trial (NCT04181723), a randomised, double-blind, placebo-controlled trial lasting 12 weeks in 187 girls and women aged 5 to 20 years with typical Rett syndrome and a documented pathogenic MECP2 variant (93 trofinetide, 94 placebo) [35,37]. Both coprimary endpoints were met: on the RSBQ behavioural scale (Rett Syndrome Behaviour Questionnaire, 45 caregiver-completed items, 0–90 points), mean change from baseline was −4.9 with trofinetide and −1.7 with placebo (difference −3.1; 95% CI −5.7 to −0.6); on the Clinical Global Impression–Improvement scale (CGI-I, 1 to 7 points), the mean at 12 weeks was 3.5 versus 3.8 (difference −0.3; 95% CI −0.5 to −0.1); the secondary non-verbal communication endpoint (CSBS-DP-IT Social) improved with a difference of 1.0 point [35,37]. The effect is therefore statistically significant and modest in magnitude.

Sources: FDA label and European Summary of Product Characteristics (SmPC) [36,37]. US data for ages 2 to 4 years were based on extrapolation and an open-label study in girls aged 2 to 5 years [36,78]. The European SmPC recommends regular reassessment of continued benefit [37].

Adverse effects and management. In the controlled trial, diarrhoea occurred in 80.6% (mean onset on day 7, mean duration 51 days; mild in 52%, moderate in 45.3%, severe in 2.7%) and vomiting in 26.9% (mean onset on day 20) [37]. In extension studies up to 144 weeks, 53.3% had persistent or recurrent diarrhoea despite interruption, dose reduction or antidiarrhoeals, and 43.3% discontinued the drug because of adverse reactions (diarrhoea 25.8%, vomiting 6.7%, seizures 2.8%, weight loss 2.2%, decreased appetite 2.2%) [37]. In the US label, weight loss exceeding 7% occurred in 12% with trofinetide versus 4% with placebo, and vomiting was associated with aspiration and aspiration pneumonia [36]. Other frequent reactions are decreased appetite, irritability and seizures [37]. Management includes stopping laxatives before initiation, monitoring hydration and weight, not repeating a dose after vomiting, and interrupting, reducing or discontinuing treatment for severe diarrhoea, suspected dehydration, severe vomiting or significant weight loss; the effect of dose reduction on efficacy is uncertain, and resumption of the recommended dose should be considered [36,37]. A case of trofinetide-induced enterocolitis syndrome in a child was published in 2026 [79], as was a report of seizure reduction in a treated adult woman [80].

7.3. Ganaxolone in CDKL5 deficiency disorder

Ganaxolone is a methylated analogue of the endogenous neurosteroid allopregnanolone that positively allosterically modulates GABA-A receptors at a binding site distinct from benzodiazepines and barbiturates; GeneReviews classifies it as a targeted CDD therapy, the first approved for CDD seizures [3,34]. The phase 3 Marigold trial (NCT03572933) included 101 patients aged 2 to 19 years (79.2% female), with at least 16 major motor seizures per 28 days and failure of at least two antiseizure medications, randomised to ganaxolone or placebo added to up to four medications (most frequently valproate, levetiracetam, clobazam and vigabatrin), with a 6-week baseline and 17 double-blind weeks [33,34]. In the 13-week maintenance phase, median change in major motor seizure frequency was −29.4% with ganaxolone versus −6.5% with placebo (p=0.0097), and the response rate (reduction ≥50%) was 30.6% versus 12.0% [34]. The open-label extension showed a sustained effect for two years [81]. GeneReviews characterises the effect as a modest reduction in seizure burden, with somnolence as the main adverse effect [3].

Sources: European SmPC and FDA label [34,82]. US and European titration schedules differ, so the official document for the prescribing country must be followed.

Adverse effects and management. The most frequent trial reactions were somnolence (29.4%) and pyrexia (23.5%), with sedation, fatigue and ataxia; somnolence is dose-dependent and potentiated by central nervous system depressants and alcohol; the daily dose may be distributed unequally to control it, provided that the daily total is maintained [34]. As with all antiseizure medications, there is a warning for suicidal behaviour and ideation, and withdrawal must be gradual to avoid increased seizures and status epilepticus [34,82]. In February 2025, NICE (National Institute for Health and Care Excellence) did not recommend ganaxolone in the English National Health Service because of uncertainty in cost-effectiveness estimates, maintaining treatment for those already receiving it; availability therefore varies between jurisdictions [83].

7.4. Symptomatic treatment by system

Table compiled from the GeneReviews chapters, the consensus recommendations and the Oxford Desk Reference [1–4,17,47,71]. None of the antidyskinetic drugs cited for FOXG1 syndrome has an approved indication for this syndrome, so their use is off-label [4]. Augmentative and alternative communication devices do not hinder speech development [1]. GeneReviews mentions “low-dose” risperidone without specifying the dosage [1]; in the absence of a guideline dose, the dosage is extrapolated from the label for an analogous condition. In the US label (irritability associated with autistic disorder, 5–17 years), risperidone is started at 0.25 mg/day (< 20 kg) or 0.5 mg/day (≥ 20 kg), increased on day 4 to 0.5 or 1 mg/day and thereafter at intervals of ≥ 2 weeks, with an effective range of 0.5–3 mg/day, no maximum dose defined in the source for this indication and no dosing data below 15 kg [84]; in the European SmPC (persistent aggression in conduct disorder, 5–18 years, up to 6 weeks), 0.5 mg/day (≥ 50 kg) or 0.25 mg/day as oral solution (< 50 kg), with increases of 0.5 or 0.25 mg/day no more often than every other day and a usual optimal dose of 1 mg/day or 0.5 mg/day, respectively (up to 1.5 mg/day or 0.75 mg/day in some patients; no maximum dose defined in the source) [85]. Prolonged-release melatonin (Slenyto®) is taken 0.5–1 hour before bedtime, with or after food: 2 mg, increasing to 5 mg if the response is insufficient, maximum 10 mg, with assessment of the effect after at least 3 months and reassessment at least every six months [86]. Outside these ages and indications, use is off-label.

Scoliosis. The consensus guidelines of Downs and colleagues (2009) guide clinical and radiographic surveillance, positioning and spinal fusion surgery in Rett syndrome [55]. In a Brazilian study, carers of patients with Rett undergoing spinal fusion reported satisfaction with the outcome [18].

Epilepsy according to the French protocols. None of the four PNDS (French National Diagnosis and Care Protocols) proposes a specific antiepileptic regimen, and the choice depends on the seizure type described by the family, ideally documented by video-EEG [12–15]. In Rett syndrome, because focal and generalised seizures coexist, broad-spectrum drugs are recommended, mainly valproate and lamotrigine, with efficacy described for topiramate and levetiracetam in myoclonic forms; drug resistance (beyond second line) affects 16–19% of patients with epilepsy; valproate increases the risk of osteopenia, which does not increase with lamotrigine, topiramate, vigabatrin or carbamazepine; GABAergic drugs require caution in patients with breathing disturbance; the ketogenic diet is considered probably beneficial, preferably in patients with a gastrostomy, because of adherence difficulties; and vagus nerve stimulation, in 10 reported patients, reduced seizures by 50% in six and by 25–30% in two at 12 months, without respiratory worsening [12]. In MECP2 duplication, valproate, lamotrigine and ethosuximide are preferred to carbamazepine and oxcarbazepine, which may increase certain seizures; drug resistance is high in adolescence; for multiple daily seizures with falls (atonic seizures or spasms), vagus nerve stimulation, callosotomy or the ketogenic diet are discussed case by case, with a protective helmet; and there should be a prolonged-seizure protocol with buccal or rectal benzodiazepine, with monitoring for rash on lamotrigine [13]. In CDD, one study described benefit from first-line vigabatrin for spasms, and corticosteroids and ACTH are debated because of low efficacy and risks in this context, with no evidence that vigabatrin should be continued if spasms persist in the older child; the drugs with the greatest seizure reduction at 3 months were felbamate, vigabatrin, clobazam, valproate, lamotrigine and zonisamide, and those with more modest efficacy were levetiracetam, rufinamide, phenobarbital, corticosteroids and ACTH [14]. In a retrospective series of 39 children with CDD, the response rate (≥50% reduction with at least one drug) was 69% at 3 months, 45% at 6 months and 24% at 12 months, and only 5% were seizure-free for more than 3 years; the ketogenic diet reduced seizures in 50–60% of children over one year of age, but with escape at 6 months in 83% and at one year in 92% and adverse effects in 30%; of the 38 patients with a vagus nerve stimulator in a survey of 222 families, about 70% reported a reduction in seizures; and, in unpublished data from the international database, 7 of 10 patients improved after callosotomy, two seizure-free for more than 6 months [14]. The protocol recommends that, if seizures persist beyond second line, the choice should pass to a paediatric epileptologist (or an epileptologist after 12 years) and that polytherapy should be maintained only with significant and lasting benefit [14]. In FOXG1 syndrome, in the face of drug resistance, the aim is quality of life and the impact of seizures rather than their number, favouring dual therapy and avoiding overtreatment; the ketogenic diet and vagus nerve stimulation have not been studied [15]. In France, patients with CDD could join the national therapeutic cannabis experiment conducted by the rare epilepsy reference centres [14].

Movement disorders in FOXG1 syndrome. The French protocol adopts the treatment of dyskinesia in cerebral palsy as a model, because dystonia, choreoathetosis and hyperkinesia are, as a rule, resistant to most drugs [15]. The authors' experience suggests greater benefit from tetrabenazine than from trihexyphenidyl in disabling hyperkinesias, without proven efficacy; trihexyphenidyl reduces dystonia in some children but may worsen choreoathetosis; levodopa was effective in some cases; baclofen is the most widely used but has little efficacy; benzodiazepines are limited by sedation and hypersalivation; and, by analogy with cerebral palsy, carbamazepine or amantadine may be proposed; there is no reported experience with botulinum toxin, intrathecal baclofen or deep brain stimulation [15].

Nutrition and reflux. The protocols recommend dietetic assessment of the growth curve, oral feeding skills and intake at diagnosis and at least once a year, with a BMI target close to the 25th centile of the general population (corresponding to the 50th centile of the Rett syndrome-specific charts), a high-calorie and calcium-enriched diet if growth slows, and adapted textures (minced or ground if chewing is weak without dysphagia, puréed if there is dysphagia or no chewing) [12,14,15]. Gastrostomy is discussed in a multidisciplinary meeting in the case of BMI below the 3rd centile despite a high-calorie diet, aspiration with pneumonia, excessively long meals (more than 1 hour in CDD, more than 45 minutes in FOXG1 syndrome) or, in FOXG1 syndrome, severe reflux; gluten-free or lactose-free diets do not improve growth [12,14,15]. The CDD protocol adopts the ESPGHAN undernutrition criteria for children with multiple disabilities (one is sufficient: physical signs such as pressure sores or poor peripheral circulation, weight-for-age < −2 Z, triceps skinfold or mid-upper arm circumference below the 10th centile, weight loss or a flat weight curve) and estimation of height from knee-heel length [14]. Reflux is treated from the first direct signs (regurgitation, vomiting, grimacing during meals) or indirect signs (bruxism, crying or discomfort at night, sleep disturbance), with a proton pump inhibitor as first line, addition of an H2 antagonist if this fails and, in severe resistant reflux, bethanechol (hospital pharmacy) introduced gradually, if there is no unstable epilepsy or asthma; if treatment fails, endoscopy and possible antireflux surgery [12,15]. The CDD protocol recommends confirming reflux by pH monitoring before the proton pump inhibitor and allows bethanechol if seizures are reasonably controlled [14]. The H2 antagonist named in 2017 and 2018, ranitidine, was suspended in the European Union in 2020 [88]. For constipation, the protocols recommend laxatives, hydration, fibre and combating immobility, and education of carers about the signs of obstruction [13,14].

Respiratory problems and infections. Prevention relies on combating food aspiration and reflux, vaccination against seasonal influenza and pneumococcus and, for sialorrhoea, head positioning, scopolamine (hyoscine) patches and botulinum toxin injected into the salivary glands [12,14,15]. In children with severe congestion or aspiration pneumonia, it is recommended to stop oral feeding, place a gastrostomy and use a secretion suction device, with intensified chest physiotherapy, prone positioning for nocturnal drainage and, in some cases, cough-assist or intrapulmonary percussion devices taught to the parents; no drug has been shown to be effective, but inhaled anticholinergics and bronchodilators (and inhaled corticosteroids, in CDD) have been proposed for bronchial hyperreactivity; mucolytics are contraindicated; in recurrent infections, continuous oral or inhaled antibiotic therapy may be discussed, for example in alternating courses (amoxicillin, co-amoxiclav, co-trimoxazole or macrolides); nocturnal non-invasive ventilation and oxygen therapy are decided case by case in a multidisciplinary meeting; and recurrent respiratory infections should raise the possibility of tracheobronchial compression by scoliosis [12,14,15]. In MECP2 duplication, early antibiotic therapy is recommended for respiratory infection, which can worsen rapidly; for recurrent pneumonia, alternating antibiotic prophylaxis, a secretion suction device, chest physiotherapy and non-invasive ventilation should be discussed; for severe and recurrent infections with significant immune deficiency, assessment by an immunologist from a hereditary immune deficiency centre (CEREDIH), whose recommendations guide the use of live attenuated vaccines, while the remaining vaccines are given according to the schedule; and, in the case of obstructive apnoeas, polysomnography, possible adenotonsillectomy and non-invasive ventilation [13]. The same protocol includes follow-up of pulmonary hypertension by cardiology or respiratory medicine (pulmonary hypertension reference centres), correction of strabismus and hypermetropia, dental follow-up of persistent deciduous teeth, treatment of spasticity (baclofen or botulinum toxin, prescribed by physical and rehabilitation medicine), investigation for growth hormone deficiency in marked short stature, endocrinological opinion for micropenis, cryptorchidism and precocious puberty, and surgery for inguinal hernia and cryptorchidism [13].

Orthopaedics, surgery and anaesthesia. The Rett syndrome protocol indicates scoliosis surgery at a Cobb angle of 40–50°, organised by anaesthesia, pain, epilepsy and early mobilisation teams, with prior management of nutritional and bone status; before the pubertal peak, a brace or temporary subcutaneous rods to preserve vertebral growth and, with sufficient bone maturity, definitive arthrodesis [12]. The CDD and FOXG1 syndrome protocols indicate surgery when the deformity progresses despite orthopaedic treatment or this is poorly tolerated, and prefer, before puberty, fusionless instrumentation with magnetic or mechanical growing rods to reduce the number of procedures; in FOXG1 syndrome, prevention of hip dislocation includes positioning in about 20° bilateral abduction and physiotherapy, and subluxation may require soft-tissue or bony surgery [14,15]. The most widely used orthoses are the moulded seating brace, ankle-foot orthoses, scoliosis braces, elbow orthoses and night-time knee extension orthoses, the standing frame and the moulded mattress, reviewed to detect pressure sores and adjusted for growth [12,15]. All surgery should take place in a hospital setting linked with the reference centre: anaesthetic risk is higher because of respiratory complications (post-anaesthetic apnoea or hypoventilation), the high pain threshold may delay recognition of postoperative complications, wound healing may be delayed or become infected because of stereotypies, abnormal movements and undernutrition, and scoliosis and hip surgery and percutaneous gastrostomy should be performed by teams trained in multiple disability [12,14,15].

Sleep, behaviour, pain and oral health. When behaviour changes, pain and its cause (dental, bone, digestive) or a change in the environment are sought first; the approach is multidisciplinary, with behavioural therapy, psychotropic drugs for severe agitation or anxiety and relaxation techniques in a multisensory environment (Snoezelen) [12,14,15]. Sleep is assessed with a sleep diary, actigraphy and, if necessary, polysomnography; melatonin and neuroleptics are frequently used, and the FOXG1 syndrome protocol adds sleep hygiene rules, light therapy for sleep–wake rhythm disorders and the risk of tardive dyskinesia with neuroleptics; in central or obstructive apnoeas and hypoventilation, oxygen or non-invasive ventilation is discussed [12,15]. Dental care can be provided under an equimolar mixture of nitrous oxide and oxygen (or general anaesthesia, in FOXG1 syndrome) in adapted facilities [12,15]. Non-pharmacological interventions include early intervention and special education, active and passive physiotherapy, psychomotor therapy, music therapy, hydrotherapy, therapeutic horse riding, speech and language therapy for oral skills and non-verbal communication, psychological support for parents and siblings and, for some functional symptoms, osteopathy [12,15]. In MECP2 duplication, augmentative and alternative communication (pictograms, signs, Makaton, PECS) should begin as early as possible, and rehabilitation should be maintained and intensified after a phase of regression, with possible partial functional recovery [13].

7.5. Agents and circumstances to avoid

As people with MECP2 disorders have an increased risk of potentially fatal arrhythmias associated with long QT, drugs prolonging the QT interval should be avoided: prokinetics (cisapride), antipsychotics (thioridazine), tricyclic antidepressants (imipramine), antiarrhythmics (quinidine, sotalol, amiodarone), anaesthetics (thiopental, suxamethonium) and anti-infectives (erythromycin, ketoconazole); the complete, updated list is provided by CredibleMeds® [1]. In CDD, combinations of sedative drugs should be weighed against their effects on participation in education and therapies, sleep and quality of life [3].

The French Rett syndrome protocol adds some antiemetics (droperidol, domperidone) to the list of drugs to avoid because of QT prolongation and recommends that the list be adapted to each patient with the cardiologist; apart from long QT, there are no specific drug contraindications, but the vulnerability of these patients justifies weighing the benefit and risk of each prescription and taking particular care with respiratory depressants (benzodiazepines, opioids and derivatives), a recommendation repeated in the CDD and FOXG1 syndrome protocols, the latter including certain antiepileptic drugs [12,14,15]. Mucolytics are contraindicated in bronchial congestion in these children [12,14,15]. In MECP2 duplication, carbamazepine and oxcarbazepine may worsen some seizures, and live attenuated vaccines follow the recommendations for immune deficiency when this is present [13].

7.6. Surveillance

Sources: GeneReviews [1–4]. ADHD: attention deficit hyperactivity disorder. The follow-up intervals of the French protocols, with their sources, are given in the surveillance table in section 11.

7.7. Investigational therapies

Gene therapy in Rett syndrome. Phenotype reversibility in mouse models supports gene replacement, but MeCP2 dosage sensitivity necessitates control of transgene expression, as excess reproduces duplication syndrome [2,24]. TSHA-102 (Taysha Gene Therapies) is a non-replicating self-complementary AAV9 vector encoding a miniMECP2, administered as a single intrathecal dose; the phase 1/2/3 REVEAL study (NCT05606614, girls and women aged 6 to 21 years, 17 enrolled) and paediatric studies NCT06152237 and NCT07480564 (2 to <4 years) are active, not recruiting, with completion expected in 2031 [38]. According to sponsor releases in June and August 2026 (preliminary, non-peer-reviewed results), dosing in the pivotal REVEAL trial was completed with 17 participants at the developmental plateau stage, in an open-label, single-arm design; in part A of the phase 1/2 studies, the 12 participants (6–21 years) reportedly acquired or regained at least one developmental milestone at 12 months, without severe treatment-related serious adverse events or dose-limiting toxicities in 33 patients treated across the three studies by August 2026; results of the 6-month interim analysis and the FDA response regarding the pathway to a licence application (BLA) are expected in the first half of 2027 [89]. NGN-401 (Neurogene) is a non-replicating recombinant AAV9 vector carrying the full-length human MECP2 transgene, in a study registered as phase 3 (NCT05898620) in girls with typical Rett syndrome from 3 years, with an estimated 33 participants [39]. In August 2026, the sponsor reported that the 10 phase 1/2 participants treated with the 1E15 vg dose improved on CGI-I and gained at least one developmental milestone (mean 4.7) through 30 months of follow-up, with good tolerability in 35 patients; topline results of the Embolden registration trial are expected in the second half of 2027 [90]. These are open-label data without a control group, disclosed by press release and not yet published in a peer-reviewed journal, using a sponsor-defined composite outcome; they do not allow comparison with trofinetide or between the two gene therapies. No gene therapy is approved for Rett syndrome [36,37].

Other drugs in Rett syndrome trials. Fenfluramine is being tested in a phase 3 trial sponsored by UCB (NCT07503444; 5 to 35 years; 200 planned participants; recruitment began in July 2026), with coprimary endpoints of RSBQ and clinical global impression of change at 14 weeks, and NA-921 (Biomed Industries) in a phase 3 trial (NCT06840496; girls and women aged 5 to 20 years; 210 planned participants) with the same endpoints as LAVENDER at 12 weeks [91]. Fenfluramine is authorised only for seizures in Dravet and Lennox–Gastaut syndromes, so its use in Rett syndrome or CDD outside a trial is off-label [92]. Previous controlled trials of mecasermin (recombinant insulin-like growth factor 1) and oral ketamine showed no benefit (section 7.8) [93,94].

MECP2 duplication. In mice with duplication, antisense oligonucleotides normalising MeCP2 levels reversed the behavioural and electroencephalographic phenotype [95]. The antisense oligonucleotide ION440 (Ionis), administered by intrathecal bolus injection, is in a phase 1/2 sham-procedure-controlled trial (ATTUNE, NCT06430385; 2 to 65 years; estimated 48 participants; recruiting) [40]. The 2020 GeneReviews reported no trials for this syndrome [2].

CDD. Soticlestat (TAK-935; NCT03694275), ataluren for nonsense variants (NCT02758626), fenfluramine (NCT03861871 and phase 3 study NCT05064878, with 87 participants, active, not recruiting), cannabidiol, ketogenic diet, vagus nerve stimulation and bexicaserin (LP352) in DEE have been studied; protein and gene replacement therapies have been proposed [3,96]. A phase 3 ganaxolone trial between 6 months and 2 years (NCT05249556), now sponsored by Immedica, is registered with 20 planned participants and an estimated start in March 2027 [91,96]; primary completion of the phase 3 fenfluramine study in CDD is expected in November 2027 [91]. None of these drugs has an approved indication for CDD; fenfluramine approvals concern other epilepsy syndromes [3].

FOXG1 syndrome. A phase 1/2 trial of FRF-001 gene therapy, an AAV9 vector administered by intracerebroventricular injection, sponsored by the FOXG1 Research Foundation, is under way (NCT07293546; 2 to 20 years; estimated 12 participants; invitation-only enrolment began in July 2026) [91,97].

7.8. Pivotal and negative trials

These trials do not allow interventions to be ranked against one another. Trofinetide and ganaxolone were studied in different diseases, populations and outcomes (caregiver-assessed behaviour and clinical global impression in one case; seizure frequency in the other), and their effects are modest: in LAVENDER, the difference in RSBQ (0 to 90 scale) was approximately 3 points, with Cohen's d of 0.37, and CGI-I means in both groups (3.5 and 3.8) lay between “minimally improved” and “no change” [35]. In Marigold, the median change of approximately −31% is a median of individual changes, not the expected reduction in each patient, and approximately 31% of treated patients (versus 12% with placebo) achieved at least a 50% reduction; the −29.4% versus −6.5% figure in the European SmPC concerns the 13-week maintenance phase rather than the published primary endpoint [33,34]. Negative mecasermin and ketamine trials, the lack of a controlled trial below 5 years (the US indication from 2 to 4 years rests on extrapolation and an open-label study) and the absence of control groups in gene therapy studies—whose “milestones gained” outcomes are susceptible to expectation effects and variability in natural history—must be considered before extrapolation [36,93,94]. Indirect comparison between trials, or between the releases for the two gene therapies, is invalid.

7.9. Comparative regulatory status and hierarchy of evidence

The hierarchy of evidence distinguishes peer-reviewed publication (LAVENDER, Marigold, negative mecasermin and ketamine trials), sponsor press release or preliminary result (TSHA-102 and NGN-401 gene therapy data), the opinion of the Committee for Medicinal Products for Human Use (CHMP)—the trofinetide opinion was adopted on 25/06/2026 and did not itself constitute authorisation—and the European Commission or FDA decision. Authorisation does not guarantee marketing, price, reimbursement or access in each country: NICE did not recommend ganaxolone for use in the English National Health Service, and marketing dates and reimbursement for trofinetide and ganaxolone in Portugal (INFARMED), or their registration in Brazil (ANVISA), were not verified in the sources consulted [37,83].

Sources: Drugs@FDA, US labels and EMA SmPCs and medicines data file, consulted in October 2026.

Regarding US patent protection, Neuren, the trofinetide licensor, reported to the Australian Securities Exchange (ASX) on 29/09/2026 that its partner Acadia Pharmaceuticals had announced issuance by the United States Patent and Trademark Office of a Notice of Allowance for patent application no. 17/590,496 (“Methods and Compositions for Treatment of Rett Syndrome”), covering the weight-banded trofinetide dosing regimen in Rett syndrome [101]. This is an allowance decision rather than an already issued patent: according to the release, the patent should issue after the usual administrative procedures and, including six months of paediatric exclusivity, should protect trofinetide in the US until 28/03/2041, almost five years beyond the method-of-use patent for Rett syndrome, which expires in July 2036 [101]. These data come from a company release and do not change the indication or access to the medicine.

Off-label use depends on label wording, age and jurisdiction, and differs from evidence extrapolation. Trofinetide in a 3-year-old is on-label in the US and off-label in the EU, whereas use in a boy with mosaic Rett syndrome or in a patient with atypical Rett falls within the wording of the US label (which does not restrict genotype) but rests on extrapolation, as these populations were not studied [35,36]. For seizures in MECP2 duplication, FOXG1 syndrome or Rett syndrome, ganaxolone is off-label, and antiseizure and antidyskinetic drugs used in these conditions are selected by extrapolation from other epilepsies and movement disorders, without specific trials [1, 2, 4].

7.10. Divergences between the French protocols and other sources

Frequency divergences mainly reflect small series, recruited in centres and from different periods, rather than population differences.

7.11. Therapeutic education and emergencies

The French protocols treat therapeutic education as part of care, organised by a coordinator attached to the paediatric neurology clinic (a “two-voice” consultation), with an educational diagnosis, individual interviews and follow-up by telephone or e-mail [12,14,15]. The aims are to understand the disease and the treatments, to know how to act in daily life, to avoid complications and to master the technical procedures (secretion suction, airway clearance manoeuvres, feeding, positioning and management of abnormal movements); the sessions offered cover feeding and digestive disorders, constipation, respiratory disorders, abnormal movements, paroxysmal events and seizures, daily care, adaptation of the environment and transition to adulthood [12,14]. The MECP2 duplication protocol specifies the content for carers: recognising a seizure (loss of consciousness, head drop, absence, unusual movements or behaviours), placing the child in the recovery position, giving the emergency benzodiazepine if the seizure lasts more than 5 minutes and calling the emergency medical service if it persists, according to a personalised emergency protocol that can be passed to the emergency service as a “patient with special needs” record; protecting against falls; for fever above 39 °C, applying antipyretic measures and seeking assessment if it persists for more than 48 hours or is accompanied by cough, dyspnoea or signs of pain (agitation, withdrawal); recognising the signs of intestinal obstruction; and knowing how to use and adjust the gastrostomy, continuous positive airway pressure, the secretion suction device and non-invasive ventilation [13]. The protocols also recommend anticipating emergency and decompensation situations (severe or prolonged seizures, fever or sepsis, pain, shock, agitation and, in FOXG1 syndrome, worsening of abnormal movements into a dystonic or dyskinetic state) with a care plan discussed within the team and with the family [12,14,15]. There is no specific emergency card in these protocols.

8. Reproductive Options and Family Counselling

8.1. MECP2 disorders (point variants and deletions)

Inheritance is X-linked; more than 99% (approximately 99.5%) of cases are simplex, due to a de novo variant or parental germline mosaicism [1]. More than 99% of variants arise de novo, usually on the paternal chromosome, explaining the predominance of affected girls; the Brazilian source reports that rare familial cases may be inherited from the father through germline mosaicism [17,18]. Testing is recommended for both parents of an affected girl and the mother of an affected boy (the father of an affected boy is not a carrier and does not require testing) [1]. A heterozygous mother may be asymptomatic or mildly affected owing to favourable X inactivation; in that case, transmission risk is 50% in each pregnancy: daughters inheriting the variant have a high risk of disease, with severity modulated by X inactivation, and sons may have severe neonatal encephalopathy or, if they survive the first year, severe intellectual disability [1]. When the variant is not detected in parental leukocytes, recurrence risk is low but above the population risk: maternal germline mosaicism has been described in one of nine pregnancies and paternal germline mosaicism in five fathers of affected girls in 21 families [1]. Prenatal diagnosis should therefore be offered to a couple who have had an affected child even if neither parent is a carrier in blood [1]. The Oxford Desk Reference emphasises that, as familial cases are rare, recurrence risk should be weighed against the risk of an invasive procedure, although many couples wish to test a subsequent pregnancy for reassurance [17].

Once the variant is identified, testing should be offered to all first-degree female relatives regardless of clinical status, as apparently healthy sisters may be carriers with skewed inactivation and transmit the variant [1,17]. Severely affected women do not reproduce; mildly affected women have had children (50% risk); affected men do not reproduce [1]. The phenotype of a female fetus with an MECP2 variant is unpredictable, ranging from apparently normal to severely affected [1]. Preconception counselling, consideration of preimplantation genetic testing and DNA banking for probands without a molecular diagnosis are recommended [1].

The 2017 French protocol, which deals jointly with MECP2, CDKL5 and FOXG1 variants, estimates the recurrence risk for the parents of a child with a de novo variant at about 1%, because of possible germline mosaicism, and considers this risk very low when absence of the variant in both parents is confirmed [12]. A genetics clinic appointment is indispensable, without having to coincide with disclosure of the diagnosis, but becomes urgent if there is an ongoing pregnancy; parental blood samples should reach the laboratory that made the diagnosis before the appointment; and prenatal diagnosis by chorionic villus sampling or amniocentesis may be offered to the mother and, possibly, to a new partner of the father [12]. In MECP2 and CDKL5 encephalopathies, the protocol recommends testing asymptomatic sisters for the familial variant, as they may exceptionally be heterozygous with skewed X inactivation [12].

8.2. MECP2 duplication syndrome

Unlike point variants, most boys with an interstitial duplication inherit it from a heterozygous mother, generally asymptomatic owing to extreme or complete skewing of X inactivation; de novo duplications have nevertheless been described [2,10]. Smith's indicates that most unbalanced translocation cases are de novo, but parental karyotypes and FISH must exclude predisposing rearrangements [47]. Maternal assessment includes duplication testing and karyotyping to investigate a balanced translocation involving Xq28 [2]. If the mother carries an interstitial duplication, the risk is 50% per pregnancy: boys inheriting it are affected (50% risk for male offspring) and girls are usually asymptomatic, although they rarely have presentations ranging from neuropsychiatric symptoms and mild ID to a male-like phenotype, not predictable by blood X inactivation [2,47]. If the mother has a balanced translocation, risk depends on the specific rearrangement [2]. A mother with two affected sons without a detectable duplication probably has germline mosaicism; in a simplex case with negative maternal testing, risk is low but above the population risk [2]. Maternal aunts and their offspring may be at risk [2]. X-inactivation analysis in amniocytes is uninformative because the pattern does not necessarily correspond to that of the fetal brain [2]. No affected man has reproduced [2].

The 2019 French protocol describes the prenatal diagnosis pathway for a carrier mother: fetal sex determination in maternal blood at around 10 weeks of gestation, after ultrasound dating, and, if the fetus is male, chorionic villus sampling at around 12 weeks with targeted testing for the duplication by FISH, quantitative PCR or MLPA [13]. For a female fetus of a carrier mother there is no recommendation, because no correlation has been established between X inactivation, the size of the duplication and severity in the rare symptomatic girls, and requests are decided case by case in a multidisciplinary prenatal diagnosis centre; preimplantation genetic testing may be technically difficult depending on the size of the duplication and should be discussed beforehand with a preimplantation diagnosis centre [13]. When the mother is not a carrier, the theoretical recurrence risk is about 1%, because of germline mosaicism, which may justify prenatal diagnosis [13]. In France, the carrier mother is informed of the need to pass the information on to relatives at risk, directly or by authorising the physician to do so (Decree No. 2013-527), and a second appointment after disclosure, devoted to counselling the couple and the maternal line, is recommended [13].

8.3. CDKL5 deficiency disorder

About 99% of cases are simplex, owing to a germline or, rarely, post-zygotic de novo variant; rarely the variant is inherited from a heterozygous or mosaic mother with favourable X inactivation, and non-skewed X inactivation in blood does not exclude skewing in the brain [3]. Testing of the mother is recommended; the father does not need to be tested [3]. If the mother is a carrier, the risk is 50%: heterozygous daughters at high risk of disease and hemizygous sons almost always severely affected [3]. Presumed maternal germline mosaicism has been described in families with sibling recurrence, so prenatal diagnosis is offered even when maternal testing is negative; the Oxford Desk Reference reports one case of gonadal mosaicism [3,17]. Affected individuals do not reproduce [3]. The 2021 French protocol considers counselling reassuring when phenotype and genotype are consistent, recommends confirming that the variant is de novo (maternal somatic mosaicism may exist), points out that the risk is not zero because of germline mosaicism and allows prenatal diagnosis in a subsequent pregnancy; in affected boys the variant is frequently somatic mosaic, and the hypothesis of early male lethality to explain the female predominance has not been confirmed [14].

8.4. FOXG1 syndrome

Inheritance is autosomal dominant, almost always de novo; rarely the variant is inherited from an unaffected mosaic parent, and sibling recurrence has been described in two families owing to presumed parental mosaicism [4]. Testing of both parents is recommended; if the variant is not detected, the recurrence risk is slightly higher than that of the general population because of possible germline mosaicism, and prenatal diagnosis or preimplantation genetic testing may be considered [4]. There are no reports of reproduction by affected individuals, but each child would have a 50% risk; penetrance is considered complete [4]. The 2018 French protocol states that the patient's siblings, uncles and aunts and other relatives are not at increased risk, that the parents' risk is higher when somatic mosaicism has been confirmed in one of them or there is a complex parental chromosomal rearrangement, and that counselling is similar for 14q12 deletion and duplication, unless a parent carries a rearrangement predisposing to imbalance, in which case the risk depends on the type of rearrangement [15].

8.5. Prenatal diagnostic methods

Once the familial alteration has been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible; in de novo dominant diseases, non-invasive prenatal diagnosis may be appropriate in some services [1–4,62]. Different perspectives among professionals and families regarding prenatal diagnosis should be discussed [2,3].

9. Special Considerations: Population Diversity and Epidemiology

Worldwide Rett syndrome prevalence is 1:10,000 to 1:23,000 female births [1]. The meta-analysis by Petriti and colleagues (10 studies, 9.57 million females, 673 cases, studies from 2000 to 2021 also searched in LILACS) estimated a pooled prevalence of 7.1 per 100,000 females (95% CI 4.8–10.5), consistent with 5 to 10 per 100,000 [9]. The Oxford Desk Reference reports 1/12,000 female births for the classical form, and the Brazilian source 0.88 per 10,000 girls [17,18]. Available incidence estimates are 0.43–0.71 per 10,000 females in France, 0.586 per 10,000 in Serbia and 1.09 per 10,000 in Australia [1]. Rett syndrome occurs in all populations and has no known founder effect, consistent with its de novo origin at CpG hotspots [1,22].

For MECP2 duplication syndrome, birth prevalence in Australia is 0.65 per 100,000 live births and 1 per 100,000 boys, with median age at diagnosis 23.5 months (birth to 13 years); microarray studies suggest approximately 1% of boys with moderate to severe ID, whereas the Oxford Desk Reference estimates ~2% of boys with severe ID [2,10,45]. A Chinese series of 16 patients from 16 families has been described [47]. For CDD, incidence of 2.36 per 100,000 live births (95% CI 0.805–5.59) derives from four cases among 333 Scottish children with epilepsy investigated by panel over three years; prevalence in the general population is unknown and Orphanet records birth prevalence of 1–9/100,000 in Europe [3,7,11]. For FOXG1 syndrome there are no prevalence data; the International FOXG1 Foundation estimates approximately 1,000 diagnosed people worldwide, and Orphanet records prevalence below 1/1,000,000 for the 14q12 microdeletion form [4,8].

The French protocols add their own estimates, all derived from the literature rather than national registries: prevalence of Rett syndrome of 1/10,000 to 1/22,000 female births depending on the region, with Rett syndrome as the leading cause of intellectual disability in females after trisomy 21; prevalence of atypical Rett of about 1/45,000, assuming that 32% of cases are atypical; incidence of CDD between 1/40,000 and 1/60,000, one of the most frequent genetic causes of developmental and epileptic encephalopathy; MECP2 duplication in about 1% of X-linked ID, with unknown incidence; and unknown incidence of FOXG1 syndrome, which affects both sexes in all regions, with fewer than five adults recorded in France [12–15]. The French estimate of CDD incidence (1.7–2.5 per 100,000) is compatible with the Scottish incidence of 2.36 per 100,000, obtained in a small population cohort with a wide confidence interval [11,14].

Regional gaps. No population-based prevalence or incidence studies for Rett syndrome, MECP2 duplication, CDD or FOXG1 syndrome in Portugal, Brazil, other Latin American countries, Africa or the Middle East were found in the consulted sources; available Brazilian data are clinical and molecular series, such as the 105-patient series with 64.1% point variants [43]. The worldwide meta-analysis included Latin American databases, but its eligible studies do not allow regional estimates [9]; case series measure variant distribution in a referred population rather than prevalence, and the absence of studies in the consulted sources does not demonstrate that none exist. There are also no prevalence estimates for PPM-X or MECP2 neonatal encephalopathy.

Special populations. In males, classical Rett syndrome occurs mainly with a 47,XXY karyotype or somatic mosaicism [1,46]. Although predominant in females, CDD affects both sexes with comparable severity, and recognising boys with CDD requires avoiding its consideration as a “girls' disease” [3]. Adults with FOXG1 syndrome and MECP2 duplication are likely under-recognised because they have never undergone genomic testing [4].

10. Illustrative Clinical Case

10.1. Girl with classical Rett syndrome (composite teaching case)

A 26-month-old girl, the second daughter of non-consanguineous parents, is referred for loss of words. Pregnancy and delivery were uneventful and head circumference at birth was on the 50th centile. She sat at 7 months, crawled at 10 and said her first words at 12 months. From 15 months her parents noticed less interest in toys and, between 18 and 22 months, she stopped using words, stopped grasping a spoon and began rubbing her hands at the midline and mouthing them while awake. She had a period of irritability, inconsolable crying and social withdrawal. On examination, head circumference had fallen to the 3rd centile, and hand-wringing stereotypies, episodes of hyperventilation followed by apnoea, bruxism, a broad-based dyspraxic gait, cold hands and feet and intense eye contact were observed. Brain MRI and metabolic screening were normal; EEG showed epileptiform activity during sleep. Meeting the regression criterion, all four main criteria and exclusion criteria, she was clinically diagnosed with typical Rett syndrome [30]. MECP2 sequencing identified heterozygous c.502C>T, p.(Arg168Ter), absent in both parents. Electrocardiography showed QTc at the upper limit of normal, so the family was given the list of drugs to avoid [1]. She started physiotherapy, occupational therapy, speech and language therapy with eye-tracking communication, and nutritional and scoliosis surveillance. At 6 years, already in the stabilisation phase, trofinetide treatment was discussed, weighing the modest RSBQ benefit and diarrhoea in approximately 80% of patients, with prior laxative withdrawal and weight monitoring [35,37]. Counselling explained that the variant is de novo but germline mosaicism justifies offering prenatal diagnosis in a future pregnancy and testing the older sister [1,17]. This composite case reproduces the sequence described in the founding series of Hagberg and colleagues (35 girls with normal development until 7–18 months, stagnation and rapid deterioration) [20].

10.2. Published case: Rett phenotype in a 47,XXY boy

In 1998, Schwartzman and colleagues in São Paulo described a boy born at term, the fourth child of healthy, non-consanguineous parents, with birth head circumference 32 cm (2.5th centile) [46]. According to his mother, development was normal until 8 months—he sat unsupported, picked up objects and food and said “mummy”—but around 11 months he stopped picking up objects, stopped communicating and became withdrawn, and hand stereotypies appeared before the first year; he also had bruxism and constipation [46]. At first assessment, aged 2 years and 4 months, he had severe global delay, mild hypotonia, stereotypies with clasped hands brought to the mouth, hand apraxia, no words, broad-based axial ataxia and brief apnoeic episodes; head circumference was 45 cm (below the 2.5th centile) [46]. At 3 years and 1 month the presentation persisted, with more frequent and prolonged apnoeas, walking only with support and some improvement in interaction [46]. Karyotyping showed 47,XXY, fragile X testing was negative, and infectious serologies, cerebrospinal fluid, EEG, brain MRI and rectal biopsy were normal [46]. Figure 1 of the article shows the child with hand stereotypies and Figure 2 the karyotype, both accessible in the online version (https://doi.org/10.1590/s0004-282x1998000500020) [46]. Following gene identification, the same group demonstrated MECP2 c.423C>G, p.(Tyr141Ter), in this patient, in historical e2 isoform numbering, absent in his parents and sister—NM_001110792.2:c.459C>G, p.(Tyr153Ter), classified as pathogenic in ClinVar [42,102]. The case illustrates three points: a classical Rett phenotype in males should prompt karyotyping and MECP2 mosaicism testing; the second X chromosome permits survival and a female-like phenotype; and molecular confirmation, subsequent to the clinical description, should be reported using current and historical nomenclature [1,46,102].

10.3. Vignette: boy with MECP2 duplication

A 4-year-old boy with hypotonia from birth, feeding difficulties, constipation, three pneumonias requiring hospitalisation, absent speech and increasing lower-limb spasticity has a normal karyotype. Microarray reveals an approximately 0.5 Mb duplication at Xq28 including MECP2 and IRAK1; his mother, with a history of depression and anxiety and normal cognition, is a carrier with completely skewed X inactivation [2,47]. Counselling communicates a 50% risk per pregnancy, with affected boys and usually asymptomatic girls, and extends testing to maternal aunts; management includes early antibiotics, complete vaccination with post-vaccination pneumococcal titres, physiotherapy and surveillance for epilepsy, which begins at a median age of six years [2].

11. Prognosis and Long-Term Follow-Up

In Rett syndrome, mortality is increased (approximately 1.2% annually), partly owing to autonomic disturbance of ventilation and cardiac rhythm and seizures [17]. In the Australian registry of 396 patients followed for up to 20 years, survival probability was 77.6% at 20 years, 71.5% at 25 years and 59.8% at 37 years; the Brazilian source indicates that 70% reach 35 years and survival may extend into the fifth or sixth decade, with severe disabilities [18,54]. Death is frequently associated with a secondary, infectious cause or is sudden [18]. According to the Brazilian source, patients with point variants usually have a classical presentation, with respiratory disturbances associated with a worse prognosis, and scoliosis may worsen or cause chronic restrictive respiratory failure [18]. Among adults (median age 25 years), 71% lived with their parents; 18% walked independently and 43% with support; 64% took antiepileptic medications; 83% had constipation and 53% abdominal distension; 63% had sleep disturbance; and urinary tract infections, pneumonias and episodes of anxiety and mood disturbance were common [54]. Dependency is high and almost all adults have fixed joint deformities and scoliosis, but cognitive and communication abilities do not deteriorate with age [17,50]. Boys with severe neonatal encephalopathy frequently die before two years [1].

In MECP2 duplication syndrome, almost 40% of boys described in Smith's died before 25 years, and GeneReviews reports death before 25 years in almost 50%, mainly from respiratory infections; refractory epilepsy is associated with neurological deterioration, and many adults require a wheelchair [2,47,59]. In CDD, epilepsy remains refractory throughout life, with some improvement with age, and cerebral visual impairment may improve; transition planning for adult care should begin around 10 years [3]. FOXG1 syndrome appears to be a stable encephalopathy, without a neurodegenerative course; survival to 32 years is documented, but life expectancy is unknown [4].

Follow-up should be provided by a multidisciplinary team with at least annual review, QTc and scoliosis monitoring in MECP2 disorders, infection surveillance in duplication, seizure and vision management in CDD, and assessment of feeding safety, sleep, behaviour, mobility and family needs in all conditions (section 7.6) [1–4]. Support organisations include the International Rett Syndrome Foundation, Rett Syndrome Europe, Rett Syndrome Research Trust, Rett UK, AussieRett, CDKL5 UK, International Foundation for CDKL5 Research and International FOXG1 Foundation [1,17]. Portugal has the Associação Nacional de Pais e Amigos Rett (ANPAR) and Brazil the Associação Brasileira de Síndrome de Rett (Abre-te); for MECP2 duplication, there is Cure MECP2 Duplication Syndrome [103]. In Europe, the neurodevelopmental disorders in this article are covered by the European Reference Network ERN ITHACA, and developmental and epileptic encephalopathies such as CDD by the rare and complex epilepsy network (EpiCARE) [16].

In France, follow-up is coordinated by paediatric neurologists, neurologists or geneticists of the Déficiences intellectuelles de causes rares reference and competence centres of the DéfiScience network (including the “Rett & polyhandicap” centre of the Necker-Enfants Malades Hospital and the coordinating centre at the Pitié-Salpêtrière, in Paris) and of the developmental anomaly centres (CLAD) of the AnDDI-Rares network, in liaison with the rare epilepsy reference centres, CEREDIH for the immune deficiencies of MECP2 duplication, the pulmonary hypertension centres and, for cerebral visual impairment in CDD, the SENSGENE network [12–15]. The protocols serve as the basis for the application for exemption from co-payment as an “off-list” long-term condition, and the social worker handles the file at the Maison départementale des personnes handicapées (MDPH), the education allowance for a child with a disability (AEEH, which funds non-reimbursed rehabilitation such as psychomotor therapy and occupational therapy in private practice), schooling (personalised plan with a support assistant) and the legal protection measure at the age of majority; children and adults are cared for in medico-social facilities such as early medico-social action centres (up to 6 years), special education and home care services, medico-educational institutes, facilities for children and adults with multiple disabilities and specialised residential homes [12,13,15]. The patient organisations listed are the Association Française du Syndrome de Rett (with a CDKL5 group), the CDKL5 Alliance Francophone, the Association française du syndrome de duplication du gène MECP2, the Xtraordinaire and Les Petits MecP2 associations and the Association FOXG1 France [12–15]. The CDD protocol considers registration of patients in an international database indispensable and refers general care of multiple disability to the generic HAS PNDS dedicated to polyhandicap [14].

In adulthood, the Rett syndrome protocol draws attention to possible loss of walking, parkinsonian signs, mood and sleep disturbances and the persistence of constipation, dysphagia and aspiration pneumonia, and recommends systematic gynaecological follow-up, updating of vaccinations and the general-population cancer screening programmes (cervix, breast, colon) [12].

Surveillance table compiled from the four French protocols and the GeneReviews chapters. The protocol intervals are expert consensus without studies comparing follow-up frequencies; the internal inconsistencies regarding densitometry and ophthalmology in Rett syndrome and FOXG1 syndrome are discussed in section 7.10.

12. Summary and Concluding Remarks

The spectrum covered here brings together four conditions sharing regression or severe developmental delay, stereotypies, epilepsy and dysautonomia, but differing in gene, mechanism, inheritance and prognosis. Rett syndrome results from MECP2 loss of function at Xq28, almost always de novo on the paternal X; diagnosis is clinical, using the 2010 criteria requiring regression followed by stabilisation, and is confirmed in approximately 95% of classical forms by sequencing and deletion analysis. Duplication of the same gene causes a distinct syndrome in boys of hypotonia, severe ID, spasticity, infections and epilepsy, almost always inherited from an asymptomatic carrier mother, diagnosed by microarray rather than sequencing. CDD, previously the early-seizure Rett variant, is an X-linked DEE affecting both sexes, with seizures in the first months and cerebral visual impairment, whose diagnosis requires attention to brain transcript NM_001323289 and mosaicism. FOXG1 syndrome, previously the congenital Rett variant, is autosomal dominant and de novo, without regression, with dyskinesia and characteristic neuroimaging showing a thin corpus callosum, simplified gyration and thick fornices.

Targeted therapy has reached two of these conditions: trofinetide (Daybue®, FDA since 2023 from 2 years; Daybu®, European Union since August 2026 from 5 years) modestly improves neurobehavioural symptoms in Rett syndrome, at the cost of very frequent diarrhoea, and ganaxolone (Ztalmy®) modestly reduces major motor seizures in CDD, with somnolence as the main adverse effect. QTc surveillance and avoidance of QT-prolonging drugs, prevention and treatment of scoliosis, nutrition, augmentative communication and genetic counselling, which must address germline mosaicism in de novo forms and maternal transmission in duplication, remain the foundations of care. AAV9 gene therapies for Rett syndrome and FOXG1 syndrome and the antisense oligonucleotide for MECP2 duplication are in clinical trials, and bidirectional MeCP2 dosage sensitivity is the central challenge of these strategies. In October 2026, TSHA-102 and NGN-401 gene therapy data come from open-label studies disclosed by press release, with registration results expected in 2027, and phase 3 trials of fenfluramine and NA-921 in Rett syndrome are under way; until publication and regulatory assessment, none of these options should be presented to families as established treatment [89–91].

The four French national protocols (2017–2021) add to this picture age-specific follow-up intervals, criteria for gastrostomy and surgery, vitamin D and tetrabenazine doses, therapeutic education content and the organisation into reference centres; they are expert consensus documents predating the European authorisations, and their divergences from GeneReviews concern mainly frequencies, transition ages and densitometry intervals [12–15].

13. References

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