Rett syndrome: Genetics, clinical features, and diagnosis

INTRODUCTION — Rett syndrome (RTT) is a neurodevelopmental disorder that occurs almost exclusively in females. It was described in 1966 by Andreas Rett, an Austrian pediatrician and neurologist [1]. After a brief period of initially normal development, affected patients experience loss of speech and purposeful hand use, stereotypic hand movements, and gait abnormalities. Additional features include deceleration of head growth, seizures, autistic features, and breathing abnormalities [2]. Most cases result from pathogenic variants in the MECP2 gene [3].

This topic will review the genetics, clinical features, and diagnosis of Rett syndrome. The treatment and prognosis are reviewed elsewhere. (See "Rett syndrome: Treatment and prognosis".)

Autism spectrum disorders are discussed separately. (See "Autism spectrum disorder (ASD) in children and adolescents: Terminology, epidemiology, and pathogenesis" and "Autism spectrum disorder in children and adolescents: Clinical features" and "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis".)

PATHOPHYSIOLOGY

Genetics — In the majority of patients, RTT is caused by pathogenic variants in the MECP2 gene, which maps to Xq28 and encodes methyl-CpG binding protein 2 (MeCP2) [3]. Although MeCP2 is expressed in all tissues, it is most abundant in the brain, which may be more sensitive to abnormal MeCP2 than other tissues. Pathogenic variants in MECP2 have been detected in approximately 95 percent of classic sporadic RTT cases and 75 percent of atypical RTT cases [4,5]. A minority of patients have atypical RTT caused by pathogenic variants in the CDKL5 or FOXG1 genes, though aberrations in these genes most often cause neurodevelopmental phenotypes that are now recognized as separate disorders [6,7]. (See 'Classification and major features' below and 'Atypical RTT' below.)

There are three types of pathogenic variants in MECP2: missense, frameshift, and nonsense. The type of mutation may affect phenotypic expression. (See 'Genotype-phenotype correlations' below.)

Rett syndrome is sporadic in nearly all cases (>99 percent) and is most often due to de novo mutations in the MECP2 gene [8]. These mutations are almost exclusively of paternal origin [9]. This may explain the high female to male ratio in RTT and suggests another cause of (apparent) male sparing besides early lethality. In rare hereditary cases, the mother was either a carrier of the pathogenic variant [3,10-14] or a mosaic for the variant [3]. In one family with affected male children and a female child with classic RTT, the MECP2 variant was located on the mother's paternal X-chromosome [14].

Most individuals with RTT have random X-inactivation (also known as Lyonization) so that the normal MECP2 allele is expressed in some cells [3,15]. The normal allele appears to enable affected females to survive but does not protect them from neurodevelopmental abnormalities [3]. Random inactivation also contributes to the spectrum of phenotypes in RTT. Except in special circumstances such as Klinefelter syndrome or mosaicism, similar pathogenic variants in brothers of affected females most often result in severe neonatal encephalopathy and are lethal.

Some affected patients have nonrandom X-inactivation. In one series, this was associated with a milder phenotype or a mitigated classic RTT caused by a rare, early truncating mutation [3].

Pathogenic variants in the MECP2 gene have also been detected in other neurologic disorders. These include females with non-Rett phenotypes such as autism, females and males with nonspecific X-linked intellectual disability, and males with progressive spasticity, congenital encephalopathy with respiratory arrest, or non-fatal neurodevelopmental disorders [11-13,16,17]. (See "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Terminology' and "Autism spectrum disorder (ASD) in children and adolescents: Terminology, epidemiology, and pathogenesis", section on 'Genetic factors'.)

Mechanism — How pathogenic variants in MECP2 lead to RTT is not fully established. The leading hypothesis is that MeCP2 deficiency leads to failure of synaptic maturation and maintenance in the cortex [18-20]. MECP2 contains two functional domains, a methyl-CpG binding domain and a transcriptional repression domain [21]. MeCP2 is considered a high-level genome-wide regulator with a variety of putative functions, which include transcriptional repression and activation, modulation of transcription and retrotransposition of long interspersed nuclear elements-1 (L1s) in neurons, and promotion of gene imprinting [18,22]. Thus, it is likely that MeCP2 deficiency or loss of function causes aberrant expression of its different target genes during and after neuronal development, which results in RTT.

Genotype-phenotype correlations — There are more than 250 known pathogenic variants in MECP2 associated with RTT [23]. However, nearly 80 percent of cases are comprised of the eight most frequently identified point mutations (R106W, R133C, T158M, R168X, R255X, R270X, R294X, R306C) and C-terminal truncations.

Studies evaluating large databases or series of patients with RTT and animal models suggest that the R133C, R294X, and C-terminal truncating mutations are associated with somewhat milder disease, while the R168X, R255X, R270X, and T158M mutations are associated with more severe disease [5,24-29].

There is evidence that truncating mutations occurring before and including amino acid R270X may cause a more severe phenotype [30,31]. Although these phenotypic differences can be distinguished among RTT populations, pathogenic variants in MECP2 have broadly overlapping phenotypic variability. While their prognostic value for individual patients with RTT is limited, these data may serve as a general guide to phenotype severity [28,32].

Neuropathology — Brain growth is differentially affected in RTT. In a postmortem study of 39 patients 3 to 35 years old, most RTT brains were smaller than normal and did not grow after age four years [33]. By contrast, the heart, kidneys, liver, and spleen grew at a normal rate until 8 to 12 years of age. At that time, their growth rate decelerated but continued so that organ weights were appropriate for height, which was also reduced. Adrenal organ weights were normal.

Deceleration of brain growth in RTT begins after birth. The mechanism is uncertain but appears to reflect arrested development. This is supported by morphologic observations that include no evidence of brain degeneration, no alteration in brain weight with increasing age, lack of correlation of dendritic length with increasing age, and reduced neuromelanin in the substantia nigra [34-39].

In one study, the dendrites of pyramidal neurons were examined in six regions of the cerebral cortex in females with RTT, ages 2.9 to 35 years [40]. The cortex was selectively involved. The apical and basilar dendritic branches in layers 3 and 5 of the frontal, motor, and inferior temporal cortex were shorter compared with brains in trisomy 21 or non-Rett neurologic disorders. These findings did not change with age.

In other reports, the proteins that initiate cortical dendritic differentiation and expansion (Map2, adult form) and dendritic remodeling (cyclooxygenase) were reduced in RTT [41,42]. This indicated marked disruption of a major cytoskeletal component in the cortex. The relationship of these findings with MECP2 variants is unknown.

EPIDEMIOLOGY — RTT is a rare disorder that occurs mainly in females. In a report from a large population-based registry in Texas, the prevalence of classic RTT was estimated as 1 per 22,800 females ages 2 through 18 years, or 0.44 per 10,000 [43]. The prevalence per 10,000 females was 0.56 in France [44], 0.65 in Sweden and Scotland [45,46], and 0.72 in Australia [47].

RTT occurs in all ethnic and racial groups, and at similar rates [43,48].

CLASSIFICATION AND MAJOR FEATURES — RTT is not a degenerative disorder. Rather, it is a progressive disorder with multisystem symptom evolution over the lifespan [49]. The clinical phenotype of RTT is broad and is divided into two main categories [2]:

●Typical (classic) RTT

●Atypical (variant) RTT

Typical RTT — The clinical picture of typical (classic) RTT is unique. Affected patients initially develop normally and then experience loss of speech and purposeful hand use and onset of stereotypic hand movement and gait abnormalities. Additional manifestations can include deceleration of head growth, seizures, autistic features, intermittent breathing abnormalities, autonomic nervous system dysfunction, cardiac abnormalities, and sleep disturbances.

Females with classic RTT are typically born at term after an uneventful pregnancy and delivery. They usually appear developmentally normal for the first six months with no gross abnormalities (picture 1 and picture 2). Although some nonspecific signs may be present during the first six months [50,51], no clinically significant developmental problems typically appear during that time other than deceleration of head growth.

Deceleration of head growth beginning as early as two to three months of age is often the first sign of RTT, although this feature is not present in all individuals with typical RTT [52] and is no longer considered one of the necessary criteria for RTT [2]. At 12 to 18 months, loss of acquired fine motor, intellectual, and communicative abilities is seen (picture 3 and picture 4) [53].

In some cases, this regression is rapid, with parents or caregivers reporting "She woke up and was no longer speaking." More often, regression is slow and insidious, occurring over weeks to months with diminished interest in the surroundings and loss of purposeful hand use. During this phase, unprovoked episodes of inconsolable screaming may occur during the day or at night, disrupting sleep. These begin abruptly, may last for hours, and often provoke an exhaustive evaluation for other medical conditions if RTT has not yet been diagnosed.

In the beginning of the regression phase, stereotypic hand movements may be subtle and interspersed with purposeful hand use. They typically consist of periodic hand-to-mouth licking or grasping of the hair or clothing. Each individual develops her own distinctive unique hand pattern (picture 5). Some retain the ability to hold a cup or feed themselves in a messy, rudimentary manner.

Following the regression phase, there is a period of stabilization and some recovery of nonverbal communication, with improved eye contact and nonverbal interactions with the environment. This is later followed by a slow, insidious deterioration in gross motor function, often becoming noticeable in teenage years.

Atypical RTT — Atypical RTT is the term used for variants of RTT that have many but not all of the clinical features of typical RTT. Importantly, these variants are also characterized by a phase of regression in skills in infancy or childhood [2]. Historically, there were three defined atypical forms of RTT [2,54]:

●Preserved speech – The preserved speech variant (or Zappella variant) of RTT is a less severe form of the syndrome that is characterized by recovery of language after regression, with most girls able to speak in sentences, and generally milder expression of typical RTT features [55,56]. The majority of patients with this variant have pathogenic variants in MECP2 [55].

●Early onset seizures – The early-onset seizure variant (or Hanefeld variant) of RTT is caused by pathogenic variants in the CDKL5 gene and is characterized by a Rett-like picture with the onset of epilepsy between the first week and fifth month of life as a significant feature [57-61]. However, most pathogenic variants in CDKL5 are now recognized to lead to a distinct condition known as CDKL5 deficiency disorder and classified as a developmental epileptic encephalopathy [62]. Some cases of the early-seizure variant may also be caused by pathogenic variants in CACNA1A [63].

●Congenital – The congenital variant (or Rolando variant) of RTT caused by pathogenic variants in the FOXG1 gene [64-66] is distinct from RTT due to MECP2 variants by onset within the first six months of life.

Males with MECP2 variants — The clinical phenotype of males with pathologic variants in MECP2 includes severe neonatal encephalopathy associated with early death, atypical RTT, classic Rett syndrome, and cognitive impairment [67] The assumption that MECP2 pathogenic variants in males always causes embryonic lethality or early postnatal demise is incorrect.

A 2019 report examined the experience of the Rett Syndrome Natural History study, which enrolled over 1200 individuals with RTT, or with MECP2 variants [67]. The report identified 30 males (age at diagnosis 0.6 to 20.4 years) with MECP2 variants that spanned the entire gene, of which 27 were considered pathogenic variants. Among the 30 males, phenotypes included:

●Atypical RTT in 14 (47 percent)

●Cognitive impairment or progressive encephalopathy in 10 (33 percent)

●Neonatal encephalopathy in 4 (13 percent)

●Classic RTT in 2 (7 percent)

Nine males had died (age at death 3.2 to 29.8 years) and 21 were alive at the time of the report [67]. Compared with females with RTT, the 14 males meeting criteria for atypical RTT had a more severe clinical presentation and course, but their clinical manifestations were less characteristic of RTT; none had eye pointing, and the presence of other RTT features, such as loss of spoken language, loss of hand skills, or hand stereotypies, was variable. The investigators proposed the term "male RTT encephalopathy" as a diagnostic category for males who have a clearly identified pattern of regression, fulfill criteria for atypical RTT by meeting at least two of the four main criteria and at least five of eleven supportive criteria for RTT (see 'Clinical diagnostic criteria' below), and have pathogenic variant in MECP2.

A 2015 systematic review identified 36 studies describing 57 cases of RTT in males [68]. The cases had either a confirmatory diagnosis of RTT or clinical features consistent with typical or atypical RTT. The average age was 7.7 years, and the most common symptoms were abnormal gait/trunk movements, partial or complete loss of spoken language, head growth deceleration, and epilepsy. However, pathogenic variants in MECP2 were reported in only 65 percent of cases.

TYPICAL MANIFESTATIONS — Manifestations of RTT typically include loss of purposeful hand skills, gait and motor abnormalities, loss of spoken language, and stereotypic hand movements. (See 'Classification and major features' above.)

Additional features of RTT include:

●Growth failure

●Epilepsy

●Disorganized breathing pattern during wakefulness characterized by periods of apnea alternating with periods of hyperventilation

●Bone mineral deficit and fractures

●Autonomic nervous system dysfunction, characterized by cold feet and peripheral vasomotor disturbances

●Cardiac abnormalities

●Sleep disturbances

These are reviewed in the sections that follow.

Loss of spoken language — The majority of females with RTT lose expressive language during early childhood, although some may retain one-word expressions. They appear to communicate via eye gaze, body language, and facial expressions. However, it is often difficult to measure these behaviors using standardized instruments. A systematic review of eight studies that included 41 females with RTT (age 2 to 36 years) found some evidence of communicative behaviors for at least some individuals in each included study [69]. The authors concluded that the validity of these findings is unknown, in part because of the lack of valid measuring tools to assess communication in individuals with impairments as severe as those found with RTT.

Motor dysfunction — Extrapyramidal motor dysfunction with stereotypic hand movements and gait disturbance affects all patients with RTT. Stereotypic hand movements include opposition of hands, finger kneading and rubbing, hand clapping and washing, wringing, squeezing, twisting, and pill rolling (picture 5) [70].

The gait typically is broad-based, clumsy, and ataxic/apraxic [1,53]. Patients often have retropulsion and rock to and fro while standing or sitting. Many have difficulty crossing from one floor surface or color to another and will stop and refuse to take another step.

Extrapyramidal motor disturbances were characterized in a series of 32 affected patients, ages 30 months to 28 years [71]. Abnormalities identified in addition to stereotypic movements and gait disturbance included:

●Bruxism – 97 percent

●Excessive drooling – 75 percent

●Oculogyric crises – 63 percent

●Hypomimia – 63 percent

●Dystonia – 59 percent

●Rigidity – 44 percent

●Bradykinesia – 41 percent

●Proximal myoclonus – 34 percent

The underlying mechanism for these extrapyramidal disturbances is not known.

Scoliosis — Scoliosis is common in RTT and increases with age. By age 16, the prevalence of scoliosis in patients with RTT ranges from 50 to 85 percent [72,73].

Factors that are associated with an increased risk of developing scoliosis include inability to sit or walk unaided, lack of purposeful hand use, lack of breath holding, onset of puberty, and higher clinical severity scores [72,73].

In addition, the risk for developing scoliosis varies with genotype [72,73]. In an analysis of a large RTT database, the risk of scoliosis (after adjusting for age) was significantly increased for those with severe mutations (R106W, R168X, R255X, R270X) and large deletions [73].

Growth failure — The characteristic growth pattern of RTT consists of early deceleration of head growth, followed by deceleration of weight and height measurements [74].

This pattern of head growth deviates from growth aberrations associated with chronic disease or central nervous system or chromosomal disorders while the deceleration in ponderal growth is similar to patterns seen with acute and chronic malnutrition. Deceleration in head growth may provide the earliest clinical indicator for the diagnosis of RTT but is not required for the clinical diagnosis.

In a longitudinal study of growth in 816 females with RTT, including 726 with typical (classic) RTT and 90 with atypical RTT, the following observations were noted for growth in typical RTT [74]:

●Mean head circumference decreased below that of the normative population at one month (see "Normal growth patterns in infants and prepubertal children", section on 'Evaluation of growth'). By age two years, mean head circumference was two standard deviations below normal.

●Mean weight fell below normal by age 13 months and declined to the second percentile at age 12.5 years.

●Mean height decreased below normal by age 17 months and was two standard deviations below normal by age 12 years. However, the distribution of height in classic RTT was wide, and height above the 98^th percentile was observed in approximately 8 percent of girls with RTT.

●Pubertal increases in height and weight were attenuated.

●Poor growth was associated with greater disease severity.

Five patterns of growth were discerned in typical RTT [74]:

●Severe somatic growth failure with microcephaly (33 percent)

●Normal somatic growth with microcephaly (30 percent)

●Moderate somatic growth failure with microcephaly (19 percent)

●Normal growth (14 percent)

●Moderate somatic growth failure with normal head size (3 percent)

Compared with typical RTT, a greater proportion of patients with atypical RTT had normal growth [74].

In another study, individuals with RTT had slower rates of hand and foot growth than normal [75]. Relative to height, the rate of decelerated growth was greater for feet than hands.

Nutrition — Although multiple factors are likely responsible for the growth aberration in RTT, inadequate nutrition appears to play an important role. This may result from inadequate dietary intake, alterations in energy expenditure, and/or feeding difficulties [76].

The contribution of increased energy expenditure due to involuntary repetitive movements is uncertain. In one study, total daily energy expenditure adjusted for differences in body weight was similar in RTT and controls [77]. In another study from the same group, metabolic rates while sleeping and quietly awake were 23 percent lower in patients with RTT than controls; rates while actively awake were similar [78]. Although total daily energy expenditure was similar in the two groups, energy balance was less positive in the individuals with RTT than controls. If sustained, these small deficits in energy balance may account for growth failure. In another preliminary report, rates of amino acid loss were significantly greater in patients with RTT than controls, indicating failure to suppress endogenous body protein degradation [79].

Feeding impairment — Feeding impairment, characterized as chewing or swallowing difficulties, choking, and nasal regurgitation, frequently complicates RTT [80-86]. In addition to oromotor dysfunction, the upper gastrointestinal tract may be affected. In a study of 34 females with RTT ages 2 to 40 years, oropharyngeal dysfunction and upper gastrointestinal dysmotility occurred in 95 and 68 percent, respectively [87]. Abnormalities of oropharyngeal function included poor tongue mobility, reduced oropharyngeal clearance, and laryngeal penetration of liquids and solid foods during swallowing. Esophageal dysmotility, characterized by the absence of primary or secondary waves, delayed emptying, atony, the presence of tertiary waves, or spasm was found in 11 patients (39 percent). Gastroesophageal reflux was present in 11 patients (35 percent), including one with nasopharyngeal reflux. Six patients (20 percent) had gastric dysmotility, characterized as decreased peristalsis or atony, and one had duodenal dysmotility.

In another study, decreased dietary energy intake was associated with poor chewing and persistence of liquid and solid food residue in the pyriform sinuses and valleculae, as well as decreased body fat [85].

Epilepsy — Seizures occur in the majority of patients with RTT [88,89]. A large study from the Rare Disease Network for Rett syndrome including 528 patients (ages 8 months to 64 years) who met classic criteria for RTT reported the following [90]:

●Parent-reported seizures affected 360 patients (60 percent), and the frequency was similar for patients with classic and atypical RTT. By physician assessment of the clinical description of seizures, epileptic seizures affected 291 patients (48 percent).

●The prevalence of epilepsy increased with age. Seizures were not reported before age two years, but thereafter the proportion affected by seizures was as follows:

•2 to <5 years, approximately 33 percent

•5 to <10 years, 60 percent

•10 to <15 years, 77 percent

•15 to <30 years, 84 percent

•≥30 years old, 86 percent

●Beyond age 30, there was no increase in proportion with epilepsy, suggesting that late onset of seizures in adults with RTT is unlikely.

●In patients with RTT who are affected by epilepsy, the seizure frequency varied widely, with no seizures for six months prior to evaluation in 36 percent, monthly seizures in 27 percent, weekly seizures in 20 percent, and daily seizures in 11 percent.

●After adjustment for age, the occurrence of seizures was associated with higher scores for clinical severity of RTT.

Other smaller studies have reported a higher prevalence of seizures in RTT. As an example, a series from Sweden reported that epilepsy affected 50 of 53 patients with RTT (94 percent) [91]. Two of the nine deaths that occurred were associated with seizures (aspiration and status epilepticus). Patients had all seizure types except for typical absence and clonic seizures. The most common were complex partial, tonic-clonic, tonic, and myoclonic seizures. In this series, intractable (medically refractory) epilepsy was observed in approximately one-half of the patients.

The occurrence of epilepsy in RTT may be overestimated because affected patients have a variety of abnormal behaviors that can be mistaken as seizure manifestations [88,92,93]. These include breath holding, hyperventilation, incessant hand wringing, "vacant" episodes with sudden-absence-like freezing of activity, inappropriate screaming or laughter, and motor abnormalities (dystonia, tremulousness, and limpness). However, these events do not have associated electroencephalogram (EEG) changes. This point was illustrated by a study of video/polygraphic/EEG monitoring in 82 females with RTT ages 2 to 30 years, all of whom had epileptiform abnormalities on EEG [94]. During monitoring, 51 percent of the parents identified events that they thought represented their child's typical seizure, such as twitching, jerking, head turning, falling forward, and trembling, as well as episodes of staring, laughing, pupil dilatation, breath holding, and hyperventilation. However, only 18 percent of these clinical episodes correlated with an EEG seizure discharge. In addition, some electrographic seizures were unrecognized by parents or occurred during sleep.

Bone mineral deficit and fractures — Bone density frequently appears diminished on conventional radiographs in females with RTT, although the cause is unknown. This is seen in affected children (age two to five years) and adults, whether or not they are ambulatory. Females with RTT have abnormally low regional bone mineral density and whole-body bone mineral content [95-97]. In one study, bone mineral content was measured by dual-energy x-ray absorptiometry in 106 females with various diseases, including RTT, cystic fibrosis, juvenile dermatomyositis, liver disease, and human immunodeficiency virus (HIV) [98]. Bone mineral deficit was greatest in the patients with RTT, who all had severe abnormalities.

Individuals with RTT have a nearly fourfold increased risk of bone fracture when compared with the general population [99,100]. The risk appears to be associated with the presence of decreased bone thickness, more severe disease variants, and the use of antiepileptic medications.

Cardiac abnormalities — The annual incidence of sudden unexpected death is higher in RTT than in the general population (0.3 percent, versus 0.0001 percent for people ages 1 to 22 years) [101-103]. The mechanism is thought to be cardiac electrical instability due to abnormal autonomic nervous system regulation [104]. Increased sympathetic activity (see 'Autonomic dysfunction' below) is suggested by the increased incidence of prolonged rate-corrected QT interval (QTc) in RTT. In several reports, the incidence of prolonged QTc (>0.45 msec) was higher and heart rate variability was lower in girls with RTT than age-matched controls [102,105-107]. An increased proportion of QTc interval prolongation with advancing RTT clinical stage has been shown by some studies [102,105] but not by others [106,107]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations".)

Abnormal autonomic regulation is also suggested by a study of cardiac vagal tone, cardiac response to baroreflex, and beat-to-beat heart rate measured during rest, hyperventilation, and immediately after hyperventilation [108], and by a report demonstrating an uncoupling of breathing and heart rate control in girls with RTT [109] The authors of the latter study suggested that this uncoupling may represent a mechanism that increases vulnerability to sudden death in RTT. A deficiency in substance P in the central nervous system identified in girls with RTT may contribute to impairment of autonomic nervous system dysfunction, resulting in cardiac dysautonomia [110,111].

Autonomic dysfunction — Approximately 50 to 70 percent of patients with RTT have clinical features that indicate autonomic nervous system dysfunction with increased sympathetic tone and impaired parasympathetic response [112-114]. In addition to cardiac abnormalities and lack of heart rate variability (see 'Cardiac abnormalities' above), these include color and temperature abnormalities of the extremities (eg, the presence of cold, blue feet or hands), drooling, breathing irregularities (see 'Disorders of respiratory control' below), sweating abnormalities, episodes of pupillary dilatation, and possibly gut dysmotility.

Disorders of respiratory control — A characteristic pattern of disordered breathing during wakefulness occurs in 60 to 80 percent of patients with RTT [115-120]. This pattern consists of episodes of hyperventilation with concomitant hypocapnia alternating with hypoventilation and/or apnea. The periods of hypoventilation and/or apnea may last as long as 20 to 120 seconds and result in hypoxemia. Breathing usually is normal between these episodes. In an analysis of a large RTT database, breathing dysfunction was associated with pathogenic variants in MECP2 and clinical RTT, low body mass index Z-scores, frequency of hand stereotypies, and higher Global Clinical Severity Scores [120]. Moreover, a prolonged QTc interval was associated with severe breathing dysfunction.

Episodes of hyperventilation tend to occur when the child is excited or agitated and are frequently associated with other stereotypic movements. Apnea that occurs during wakefulness is typically central, although it may be obstructive. These events may be isolated or precede or follow hyperventilation. During apneic episodes, the child may stare quietly ahead or smile and appear happy with no evidence of distress, despite severe cyanosis.

Breathing abnormalities may cause severe hypoxemia [117]. In studies recording EEG and breathing in our laboratory, hypoxemia led to electrographic seizures only when it was associated with apnea. Seizures did not occur with disorganized breathing alone, even when oxygen saturation was as low as 30 to 50 percent. The breathing abnormalities during the awake state are not associated with bradycardia [118]. However, these events are frequently misdiagnosed as seizures. The EEG correlate may be characterized by diffuse, high amplitude slowing, a hyperventilatory response that can be mistaken for ictal electrographic changes. The EEG changes depend on severity of the episodes.

The underlying pathophysiology of disordered breathing and its relationship to the MECP2 mutation are not well-understood, but may be related to defective neuromodulation and synaptic transmission in the brainstem respiratory centers [121,122].

Breathing disturbances in patients with RTT are more pronounced during wakefulness but can also occur during sleep, including apnea, shallow breathing, hypoventilation, and increased periodic breathing [109,116,118,123].

Although data are limited, one small study using high resolution computed tomography (CT) imaging found pulmonary lesions suggestive of interstitial lung disease in approximately one-half of patients with RTT and respiratory dysfunction [124]. The pathogenesis and clinical significance of these pulmonary abnormalities is uncertain.

Sleep disturbance — Sleep disturbances affect 80 percent or more of patients with RTT, and are a problem for both the patient and caregivers [125,126]. The symptoms most commonly reported by caregivers are irregular sleep times, including prolonged periods of wakefulness or sleep, periodic nighttime awakenings with disruptive behavior (such as crying, screaming, laughing), and abbreviated total nighttime sleep with increased amounts of daytime sleep.

Sleep architecture is abnormal in RTT. In one report, the amount of rapid eye movement (REM) sleep was less than age-matched healthy controls [92].

Others — Constipation, urinary incontinence, and fecal incontinence appear to be common problems in females with RTT [127]. One study of 63 females with RTT (mean age 19 years) reported that urinary incontinence affected >95 percent and fecal incontinence affected a majority [128].

Findings from another small study suggest that gallbladder dysfunction and gallstones are more frequent in RTT compared with the general population [129].

EVALUATION — The clinical evaluation for suspected RTT includes the history, examination, and genetic testing. In some cases, additional studies may be helpful.

History and examination — A thorough history should be obtained from the parents and caregivers. Special attention should be paid to the timing of developmental milestones and the presence of a period of regression with loss of hand skills and spoken language.

Physical examination should identify the characteristic findings of RTT. Measurements typically show impaired growth. Serial measurements often show decelerating head growth, and ultimately microcephaly. A variety of neurologic manifestations may be seen, including intellectual disability or developmental delay, loss of or poor communication skills, and stereotypic hand movements. (See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis".)

DNA analysis — A clinical diagnosis of typical or atypical Rett syndrome should not be made without specialist evaluation including comprehensive genetic testing. A blood sample should be obtained for DNA analysis to identify pathogenic variants in MECP2 in a female with characteristic signs of RTT. Testing should also be considered in male infants with severe encephalopathy. The diagnosis of RTT (MECP2 positive) is made if a pathogenic variant in MECP2 is found and clinical criteria are met.

For those who have a negative analysis for known pathogenic variants in MECP2, further genetic testing should include analysis for variants in FOXG1 (if features of the congenital variant are present) and CDKL5 (if features of the early seizure variant are present) [2]. A comprehensive genetic evaluation is recommended if a pathogenic variant is not detected in MECP2, CDKL5, or FOXG1 [130,131]. Whole exome sequencing can identify variants in other genes that lead to the development of phenotypes resembling RTT [132]. Thus, in cases where the known variants are not detected, we perform whole exome sequencing; specialized genetic panels may be available such as a Rett panel. Methods of genetic testing are evolving. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Girls presenting with developmental problems of unknown etiology warrant genetic investigation and consideration of MECP2 testing if they have some features suggestive of RTT. This situation is most likely to arise for individuals <3 years old.

DNA analysis should be offered to the mother if future pregnancies are planned. Prenatal testing is available. Male siblings with neurologic or developmental disorders should also be tested. Female siblings may choose to have testing done when they reach an age at which they are able to give informed consent.

Other studies — In a child with developmental delay where no relevant pathogenic variant is identified in MECP2, CDKL5, or FOXG1, inborn errors of metabolism and neurodegenerative disorders should be considered as part of the general evaluation of(see 'Differential diagnosis' below). Suggested studies to exclude these disorders include the following:

●Brain magnetic resonance imaging (MRI)

●Serum amino acids

●Urine organic acids

●Genetic testing for Rett-like phenotypes, including Angelman and Angelman-like syndromes and/or Pitt-Hopkins syndrome if clinically suspected (see 'Differential diagnosis' below)

●White cell enzymes (if regression)

●Hearing test

●Ophthalmologic evaluation

The patient could be considered to have RTT without an MECP2 variant if these studies are nondiagnostic, clinical criteria for RTT are met, and genetic analysis has failed to identify an alternative diagnosis; however, this "working diagnosis" should be revisited periodically with repeat genetic analysis as genetic/genomic testing improves.

Electroencephalography — EEG may be helpful in the evaluation of RTT, although it is not used for diagnosis. Electroencephalography is always abnormal in RTT and shows characteristic changes. The epileptiform abnormalities typically begin at approximately two years of age [88]. The EEG subsequently deteriorates with loss of expected developmental features and the appearance of abnormal patterns [115]. These include focal, multifocal, and generalized epileptiform abnormalities, and the occurrence of rhythmic slow (theta) activity primarily in the frontal-central regions (figure 1).

Evoked potentials typically demonstrate intact peripheral auditory and visual pathways and suggest dysfunction of central or higher cortical pathways. Somatosensory evoked potentials may be characterized by "giant" responses suggesting cortical hyperexcitability.

Staging — Prior to the discovery of MECP2 and subsequent criteria revisions, a staging system was helpful to track the clinical course of RTT [133]. Today it has limited diagnostic utility, but it may be employed as a tool to anticipate potential clinical problems and provide anticipatory guidance to parents and caregivers. However, it is often difficult to discern precisely the transitions between stages. In addition, this system should not be used to predict life expectancy.

●Stage I consists of developmental arrest. The onset is between 6 to 18 months, and it may last for many months. During this time there is less eye contact, reduced play, gross motor delays, nonspecific hand wringing, and decelerating head growth (picture 1 and picture 3). Infants seem placid and not cuddly compared with healthy infants (picture 2 and picture 4).

●Stage II consists of rapid deterioration or regression. The onset is typically between one to four years of age. It may be so acute that parents and caregivers can give a specific date after which their child was no longer normal. In other cases, the onset may be insidious. The duration is usually weeks to months. This phase is characterized by the loss of purposeful hand use and spoken language, and the onset during wakefulness of hand stereotypes and periodic breathing irregularities. Hand stereotypes are most frequently midline and hand wringing or hand washing in character. They occur incessantly during wakefulness but cease during sleep, and continue into adulthood (picture 5). During this phase, many affected girls exhibit autistic behavior. Variable periods of unprovoked inconsolable crying or irritability and a disturbed sleep pattern are also common (picture 6).

●Stage III begins at 2 to 10 years of age, following the period of rapid deterioration. This phase lasts many years and is characterized by behavioral improvement and some improvement in hand use and communication skills, particularly by using "eye pointing" (picture 7 and picture 8). Motor dysfunction (picture 9) and seizures are more prominent during this time.

●Stage IV consists of late motor deterioration and usually begins after the age of 10 years. It is characterized by increased rigidity, reduced mobility, dystonia, hypomimia, and bradykinesia (picture 10). Some girls and women become non-ambulatory (picture 11) while others continue to ambulate well into adulthood (picture 12). Cognitive function is stable and interpersonal communication may continue to improve. However, spoken communication is not regained. Seizures also often improve. Quadriparesis, scoliosis, and staring may be features of this stage.

DIAGNOSIS — The diagnosis of RTT is based upon clinical and genetic characteristics. (See 'Clinical diagnostic criteria' below.)

When to suspect RTT

●Typical RTT (see 'Typical RTT' above) should be suspected in individuals who have apparently normal development in the first 6 to 18 months of life followed by regression of purposeful hand skills and spoken language along with the onset of gait abnormalities and stereotypic hand movements [2]. Postnatal deceleration of head growth should also raise suspicion for RTT, although it does not occur in all individuals with typical RTT.

●Atypical RTT (see 'Atypical RTT' above) may be suspected in individuals who have many but not all of the clinical features of typical RTT [2].

The diagnosis of typical RTT in middle childhood is usually straightforward because of the distinctive presentation, although a history that confirms a period of regression must be present. However, the diagnosis in early infancy may be more difficult. The diagnosis cannot be made definitively in the young child with decreasing head growth and delayed gross motor skills until she reaches the regression phase with loss of hand skills and spoken language, onset of hand stereotypies, and gait abnormalities. The diagnosis can usually be made in an adult female with intellectual disability and typical signs, including the prominence of motor problems with progression from a hyperkinetic to a bradykinetic state [2,134,135].

In various studies, several factors have been associated with a delayed diagnosis of RTT, including normal head size, presentation with less specific features (eg, scoliosis, bone fractures, self-abusive behavior, unusual stereotypic hand movements), age of onset of stereotypies, lack of regression of hand use or verbal language, and impaired acquisition of developmental milestones [51,136,137].

Clinical diagnostic criteria — Diagnostic criteria for RTT (table 1), revised in 2010, are divided into main, exclusionary, and supportive categories [2]. The diagnosis should be considered when postnatal deceleration of head growth is observed, although this feature is not a necessary criterion for RTT.

●Main criteria for RTT are as follows [2]:

•Partial or complete loss of acquired purposeful hand skills

•Partial or complete loss of acquired spoken language

•Gait abnormalities: impaired (dyspraxic) or absence of ability

•Stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms

●Supportive criteria for atypical RTT are the following [2]:

•Breathing disturbances when awake

•Bruxism when awake

•Impaired sleep pattern

•Abnormal muscle tone

•Peripheral vasomotor disturbances

•Scoliosis/kyphosis

•Growth retardation

•Small cold hands and feet

•Inappropriate laughing/screaming spells

•Diminished response to pain

•Intense eye communication ("eye pointing")

●Exclusionary criteria for typical RTT are as follows [2]:

•Brain injury secondary to trauma (peri- or postnatally), neurometabolic disease, or severe infection that causes neurologic problems

•Grossly abnormal psychomotor development in first six months of life

For the diagnosis of typical or classic RTT, the following are required [2]:

●A period of regression followed by recovery or stabilization

●Meet all main criteria and no exclusionary criteria

Supportive criteria are not required, although they are frequently present in typical RTT [2].

For the clinical diagnosis of atypical or variant RTT, the following are required [2]:

●A period of regression followed by recovery or stabilization

●Meet at least 2 of the 4 main criteria

●Meet at least 5 of the 11 supportive criteria

Genetic confirmation — Careful clinical assessment should be combined with appropriate genetic/genomic analysis. Detection of a pathogenic variant in the MECP2 gene confirms the diagnosis in patients who fulfill the clinical diagnostic criteria for RTT, but this abnormality is not present in all cases. Pathogenic variants in MECP2 are found in approximately 95 percent of those with typical RTT and 20 percent of atypical cases [2]. Furthermore, MECP2 variants have been identified in individuals who lack the clinical features of RTT [2]. Some individuals with an MECP2 variant who do not fulfill the criteria for either typical or atypical RTT may be classified as having a MECP2-related disorder.

DIFFERENTIAL DIAGNOSIS — Depending upon the age of presentation, the differential diagnosis of typical (classic) RTT includes the following conditions:

●Autism, hearing/visual disturbance, encephalitis, and metabolic or degenerative disorders such as neuronal ceroid lipofuscinosis, phenylketonuria, and urea cycle disorders. (See "Overview of phenylketonuria" and "Urea cycle disorders: Clinical features and diagnosis" and "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Terminology'.)

●Pitt-Hopkins syndrome, which is caused by pathogenic variants in the TCF4 gene. Characteristic features include distinctive craniofacial abnormalities (that become more apparent with age), developmental delay, intellectual disability, seizures, microcephaly, absent speech, and stereotypic hand movements [138-140].

●Angelman syndrome, which is caused by loss of function of the imprinted UBE3A gene [141,142]. Characteristic features include severe intellectual disability, postnatal microcephaly, epilepsy, sleep disturbances, and a movement or balance disorder, usually in the form of gait ataxia and/or tremulous movement of limbs. Common behavior characteristics, alone or in combination, include frequent laughter or smiling, apparent happy demeanor, an easily excitable personality, often with hand flapping movements, and hyperactivity. These manifestations continue into adolescence and adulthood, and additional features include obesity, constipation, scoliosis, limited verbal communication, and self-injurious behavior. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)'.)

●Several developmental disorders (eg, related to MEF2C pathogenic variants) may have phenotypic overlap with Rett syndrome that can cause diagnostic confusion in infants and young children [143,144].

●Spastic ataxia, cerebral palsy, spinocerebellar degeneration, leukodystrophies, neuroaxonal dystrophy, and Lennox-Gastaut syndrome. (See "Cerebral palsy: Classification and clinical features" and "Cerebral palsy: Evaluation and diagnosis" and "Overview of the hereditary ataxias" and "Autosomal dominant spinocerebellar ataxias" and "Differential diagnosis of acute central nervous system demyelination in children", section on 'Leukodystrophies'.)

●Unknown degenerative disorders.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rett syndrome".)

SUMMARY AND RECOMMENDATIONS

●Pathophysiology – Rett syndrome (RTT) is a rare neurodevelopmental disorder that occurs almost exclusively in females. In the majority of patients with typical or atypical RTT, the disorder is caused by pathogenic variants in the MECP2 gene that occur de novo (with a negative family history). Rare patients have atypical RTT caused by pathogenic variants in CDKL5 or FOXG1 genes. (See 'Genetics' above and 'Epidemiology' above.)

●Classification – The phenotype of RTT is divided into typical (classic) and atypical (variant forms). (See 'Classification and major features' above.)

•Classic – Patients with classic RTT initially develop normally and then experience loss of speech and purposeful hand use and onset of stereotypic hand movement and gait abnormalities. Deceleration of head growth can be one of the first signs. Additional manifestations can include seizures, autistic features, intermittent breathing abnormalities, autonomic nervous system dysfunction, cardiac abnormalities, and sleep disturbances. (See 'Typical RTT' above.)

•Atypical – Atypical RTT encompasses variants of RTT that have many but not all of the clinical features of typical RTT. The three defined RTT variants are the preserved speech, early-onset seizure, and congenital variants. (See 'Atypical RTT' above.)

●Evaluation – In the evaluation for suspected RTT, special attention should be paid to the timing of developmental milestones and the presence of a period of regression with loss of hand skills and spoken language. (See 'Evaluation' above.)

●Diagnosis – The diagnosis of RTT is based upon clinical and genetic characteristics. Diagnostic criteria for typical RTT require a period of regression followed by recovery or stabilization, and fulfillment of all four main criteria (loss of purposeful hand skills, loss of spoken language, gait abnormalities, and stereotypic hand movements) and no exclusionary criteria (table 1). Diagnostic criteria for atypical RTT require a period of regression followed by recovery or stabilization, fulfillment of 2 of the 4 main criteria and 5 of 11 supportive criteria. (See 'Diagnosis' above and 'Clinical diagnostic criteria' above.)

Detection of a pathogenic variant in the MECP2 gene confirms the diagnosis in patients who fulfill the clinical diagnostic criteria for RTT, but this abnormality is not present in all cases.

●Differential diagnosis – Depending upon the age of presentation, the differential diagnosis of RTT includes the following (see 'Differential diagnosis' above):

•Autism, hearing/visual disturbance, encephalitis, and metabolic or degenerative disorders

•Spastic ataxia, cerebral palsy, spinocerebellar degeneration, leukodystrophies, neuroaxonal dystrophy, and Lennox-Gastaut syndrome

•Pitt-Hopkins syndrome

•Angelman syndrome

•MEF2C-related syndromes

●Treatment – The treatment of RTT is reviewed separately. (See "Rett syndrome: Treatment and prognosis".)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledges Daniel G Glaze, MD, who contributed to an earlier version of this topic review.