Rett Syndrome

Etiology

RTT is an X-linked dominant condition with lethal consequences in hemizygous males. Recent studies have mentioned that the majority of RTT-causing variants in MECP2 are de novo and commonly occur on the paternally inherited X chromosome. The pathogenic MECP2 variants are identified in more than 95% of individuals with typical RTT. However, recent studies have found that MeCP2, the protein product of the MECP2 gene, is known to regulate gene expression and is highly expressed in the brain.[5][6]

While paternal age has been reported to be associated with an increased risk of genetic disorders, current studies revealed no significant difference in parental ages of RTT probands compared to the general population. A minimal increase in parental age has been noted with missense variants compared to those with nonsense variants. Additionally, no evident association was demonstrated between clinical severity and parental age. Therefore, advanced parental ages did not appear to be a risk factor for RTT and did not contribute to the clinical severity in individuals with RTT.[6] 

Furthermore, 2 additional genes, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1), are involved in the pathogenesis of RTT. The spectrum of mutation types includes missense, nonsense, and frameshift mutations.[7][8] Mutations affecting the NLS region of MECP2 or early truncating mutations are associated with a more severe phenotype than missense mutations, whereas C-terminal deletions are linked to milder phenotypes. The R133C mutation is generally associated with a milder variant of RTT, often with preserved speech. The MeCP2 protein is responsible for 2 main functional roles: the methyl-binding domain, which specifically binds to the methylated CpG dinucleotides, and the transcription repression domain, which recruits repressor proteins that inhibit gene transcription. Mutations in an X-linked gene, CDKL5, have been reported in patients with a seizure variant of RTT. Notably, a wide spectrum of mutations associated with disease severity has been identified, and close to 30 different types of mutations can cause RTT.[9]

A recent study on the genetic mutational spectrum of MECP2 mutations was conducted among Indian patients with RTT, revealing associations with respiratory dysfunction, scoliosis, and sleep disturbances. The significant results of this study also suggest that clinicians screen for abnormal cholesterol, calcium, and TSH levels associated with MECP2 gene mutations to facilitate early prognosis of disease severity.[10]

Current literature also suggests 4 distinct social profiles in individuals with RTT, hinting at shared disrupted circuits between sensorimotor functioning and sleep-related neuronal pathways. This study found varying degrees of social impairments and yielded the following 4 social profiles:

• Interactive motricity
• Mood change
• Anxiety/agitation
• Gazing

Furthermore, longer sleep onset latency was linked with increased sociobehavioral impairments, particularly in interactive motricity reduction. On the other hand, higher rapid eye movement sleep was connected with fewer interactive sociomotor behaviors. No significant differences were found in social profiles concerning sleep-disordered breathing or daytime sleepiness.[11]

Epidemiology

RTT is a severe, progressive, neurodevelopmental disorder that predominantly affects females and is also one of the most frequent causes of mental disability in females, with an incidence of 1 in 10,000 to 20,000 live birth cases.[5][12] A systematic review of literature described RTT as the second most frequent cause of genetic intellectual disability that can lead to neurological regression between 6 and 18 months of life and could be linked with a variety of neurological impairments along with nonneurological organs.[13]

Current data on the involvement of RTT and the endocrine system have presented growth disorders, bone health issues, thyroid abnormalities, puberty onset delays, and weight abnormalities. Another study reported the following main endocrinopathies: malnutrition, short stature, menstrual cycle abnormalities, weight disorders, low bone mineral density, hyperprolactinemia, and thyroid disorders. Furthermore, endocrinopathies were significantly more common in patients with RTT with MECP2 mutations, and epilepsy was more frequent in CDKL5 deletions.[13][14]

A population-based registry in Texas reported a prevalence of classic RTT as 1 per 22,800 females (0.44 per 10,000) from ages 2 to 18. RTT was initially thought to only occur in females, and males with RTT were not considered to be viable. Further investigations are needed on the incidence and prevalence of RTT in males. A systematic review conducted in Texas in 2015 reported 57 cases of RTT in males, and a population study showed that the incidence of RTT in males was not more prevalent in any particular racial group.[15]

Another study among females in the United States highlighted the considerable burden of RTT based on disease subtype and age. Despite a reliance on supportive therapies and healthcare encounters, patients with RTT still have increasing disease severity and motor-behavioral dysfunction in childhood and adolescence, while not meeting the needs of these patients and the value of early intervention to their long-term management.[16] 

A demographic study found that Irish patients with RTT have the same clinical presentation as those in other countries, but seizures, involuntary movements, and regression are more frequent. On the other hand, they have reported fewer skeletal deformities but with better responses to antiseizure drugs.[17]

Pathophysiology

RTT is a neurodevelopmental disorder caused by mutations in MECP2 in approximately 95% of RTT cases. MeCP2 is a non-cell-type-specific DNA-binding protein, and its mutation affects both neural and nonneural cells in the brain, including vasculature associated with endothelial cells.

Vascular integrity is essential in brain homeostasis, and its modification may be related to neurodegenerative disease pathology. Current studies have revealed a disease-specific microvascular network (Rett-dMVNs) and observed higher permeability in the Rett-dMVNs compared to isogenic controls, indicating an alteration in barrier function resulting from MECP2 mutation. Furthermore, studies have also found that hyperpermeability is linked to the upregulation of miR-126-3p in RTT patient-derived endothelial cells, as determined by microRNA profiling and RNA sequencing, and that the rescue of miR-126-3p levels can recover their phenotype. Findings also revealed miR-126-3p-mediated vascular impairment in patients with RTT, suggesting the potential application of these findings in translational medicine.[18]

Recent studies also suggested that MECP2 has both repressor and activator transcription activities. The exact mechanism of how MECP2 mutations lead to RTT is unknown. A possible theory is that a deficiency of MECP2 causes a failure of appropriate synapse maturation in the cortex. Another hypothesis is that the lack of MECP2 disrupts brain cholesterol metabolism, resulting in abnormal neuronal development. One study found that MECP2 acts as a positive cofactor for RNA Pol II gene expression at many neuronal genes that harbor CpG islands in promoter-proximal regions, and that RTT is partly due to the loss of gene activity in these genes in neurons.[19]

Recent studies have highlighted that the clinical manifestations of RTT involve an imbalance of redox homeostasis and exacerbated inflammatory responses, which underscore the role of the p75 neurotrophin receptor (p75NTR) in regulating oxidative stress and inflammation. Findings revealed that p75NTR modulation by LM11A-31 repairs protein glutathionylation and lessens the expression of the pro-oxidant enzyme NOX4. Furthermore, LM11A-31 significantly reduces the expression of the pro-inflammatory mediators interleukin-6 and interleukin-8 and regulates the expression levels of transcription factors involved in controlling antioxidant response and inflammation.[20] 

Studies have also suggested that the failure of dendritic arborization in the cortex has led to abnormal neuronal signaling, resulting in the lack of maturation of the autonomic nervous system and the motor and cortical regions. Recent evidence suggests that MECP2 is also expressed in glial cells, and glial cell dysfunction resulting from changes in DNA methylation may also contribute to the pathogenesis of RTT. The MECP2 mutation affects mitochondrial and metabolic pathways in astrocytes, thereby affecting neuronal health. The smaller mitochondria, particularly in glia versus neurons, resulted in decreased mitochondrial respiration and altered key proteins in the tricarboxylic acid cycle and electron transport chain in patients with RTT. Moreover, RTT astrocytes exhibited increased cytosolic amino acid levels under basal conditions, which decreased when energy demands were high. The mitochondria isolated from astrocytes of patients with RTT exhibited increased reactive oxygen species and influenced neuronal activity when transferred to cortical neurons.[21]

Recordings of sensory-perceptual functioning using event-related potential (ERP) approaches were identified as potentially objective tools for measuring neural function in RTT, particularly in cases of highly anomalous auditory evoked potentials (AEPs). To accurately determine the degree of neural dysfunction using the ERP technique, response reliability at the single-trial level is highly advised based on previous studies. Nonneural noise sources lead to overestimating the degree of pathological processing in RTT, and denoising source separation techniques during signal processing substantially improve this concern. On the other hand, the current study aimed to infer the neurophysiological mechanisms of auditory processing in children with RTT through auditory steady-state response (ASSR), which is related to the fine temporal analysis of auditory input, and sustained wave, which is connected with the integral processing of the auditory signal. Both processes showed potential as noninvasive electrophysiological biomarkers of auditory processing with clinical relevance, enabling the establishment of links between genetic impairment and the RTT phenotype.[22][23]

Histopathology

On autopsy, an RTT brain does not show signs of inflammation or degeneration. However, an overall decrease in brain size and the size of individual neurons is noted. A 12% to 34% reduction in brain weight has been reported, most prominent in the prefrontal, posterior frontal, and anterior frontal regions. These findings suggest that RTT is a neurodevelopmental, rather than a neurodegenerative, process. The neuronal cell size is decreased, but an increase in neuronal cell packing in the hippocampus, along with delayed neuronal maturation and synaptogenesis in the cerebral cortex, is demonstrated.

A recent study on the developmental change of brain volume in RTT in Taiwan observed a significant decrease in brain volume among patients with RTT. Furthermore, their cortical gray matter volume continues to decrease in the bilateral parietal lobes and the left occipital lobes.[24]

History and Physical

RTT is a neurodevelopmental disorder characterized by an initial period of normal growth and development, followed by regression in motor and communication skills. RTT is a clinical diagnosis; therefore, recognizing the characteristic findings of clinical assessment is essential. Key clinical features include slowed development, loss of hand function with distinctive repetitive movements, slowed brain and head growth, gait abnormalities, seizures, and cognitive impairment. Additional symptoms include irregular breathing, digestive issues, and apraxia, which affects speech and eye movements. The severity and progression of RTT vary among individuals, with some exhibiting atypical variants.[25][5]

Since RTT is still considered a clinical diagnosis, clinical features are divided into the following typical and atypical presentations:

• Typical (classic) RTT: The diagnostic criteria for a typical presentation require the presence of regression, in addition to the main criteria, and the exclusion criteria must be met (see Image. Rett Syndrome Types).
  • This category is an X-linked neurodevelopmental disorder characterized by a period of regression, partial or complete loss of purposeful hand use, and acquired speech, resulting in impairment of expressive language, hand-wringing movements, impaired gait, and ambulation, accompanied by stereotyped hand movements.[26][27] 
  • A stage of stabilization will often follow regression, and sometimes, improvement may occur. Not all individuals with typical RTT will have postnatal deceleration in head growth.
  • More than 95% of typical RTT cases have a pathogenic variant in the MECP2 gene. However, a recent case of clinically diagnosed typical RTT syndrome in an individual who lacked a genetic diagnosis despite 20 years of investigation and multiple rounds of sequencing the MECP2 gene was documented. Additional genetic testing using next-generation sequencing revealed a partial insertion of the BCL11A gene within exon 4 of MECP2, caused by a small deletion in MECP2, which may result in a possible disruption of MeCP2 function due to a frameshift.[27]

• Atypical (variant) RTT: The diagnostic criteria for atypical RTT require the presence of regression plus 2 out of the 4 main criteria in addition to 5 out of the 11 supportive criteria (see Image. Rett Syndrome Types). The above-mentioned criteria for typical RTT and atypical RTT apply to both males and females.[28][29][30]

Current studies reported the prevalence of orthopedic conditions in RTT, wherein the majority of the cases develop foot deformities, followed by scoliosis, hip displacement, and knee deformities. One study identified that age at inclusion, Cobb angle at baseline, and epilepsy have the highest discriminative ability for the rapid progression of scoliosis in RTT. In both studies, these findings can provide clinical guidelines, surveillance protocols, and management strategies for patients with RTT.[31][32][33] 

Movement disorders beyond hand stereotypies are also common, especially tremors. Hypertonia becomes more prevalent with age, accompanied by apparent changes in nomenclature over time, eg, early epoch spasticity and late epoch dystonia.[34]

Patients with RTT also have autonomic nervous system dysfunction, predominantly of the sympathetic nervous system, together with exercise fatigue and an increased risk of sudden death. A recent study demonstrated the feasibility of continuous 24-hour non-invasive home monitoring of biological vitals (biovitals) using an innovative wearable sensor device in pediatric, adolescent, and adult patients with RTT. Furthermore, the maximum heart rate and the heart rate-low-frequency ratio, indicating sympathetic nervous system activation during dynamic exercise, were identified as potential objective markers of fatigue, illness severity, and disease progression.[35]

Evaluation

The diagnosis of RTT is based on clinical observation of developmental regression, loss of hand function, characteristic repetitive movements, and other neurological and systemic symptoms, as clinicians assess early growth patterns and conduct ongoing physical and neurological evaluations. Genetic testing for MECP2 mutations supports clinical diagnosis, as over 95% of classical RTT cases and approximately 75% of atypical cases have a pathogenic MECP2 variant. Atypical RTT is diagnosed when an individual does not meet all the classical RTT criteria and may involve other genes, eg, CDKL5 and FOXG1.[5]

Therefore, MECP2 mutations alone are insufficient to diagnose RTT, and a wide variety of clinical presentations may be noted. Because of its unique characteristics, several evaluation tools of clinical severity, behavior, and functional motor abilities have been studied for RTT, including: 

• Rett Assessment Rating Scale
• Rett Syndrome Gross Motor Scale
• Rett Syndrome Functional Scale
• Functional Mobility Scale-Rett Syndrome
• Two-Minute Walking Test modified for Rett syndrome
• Rett Syndrome Hand Function Scale
• StepWatch Activity Monitor
• ActivPALTM
• Modified Bouchard Activity Record
• Rett Syndrome Behavioral Questionnaire
• Rett Syndrome Fear of Movement Scale [36]

Treatment / Management

Pharmacologic Treatment

Trofinetide is the first pharmacologic treatment approved by the US Food and Drug Administration for RTT in adult and pediatric patients aged 2 years and older. Trofinetide is a synthetic analog of glycine-proline-glutamate, the tripeptide normally split from insulin-like growth factor 1 upon degradation. Due to the presence of glutamate and glycine in its structure, trofinetide is thought to act by modulating the NMDA receptor, thereby normalizing neuronal activity and promoting survival.[37][38] (A1)

Recent clinical studies have shown that trofinetide treatment, administered at a dosage of 200 mg for 40 weeks or longer, continues to improve symptoms of RTT, offering potentially effective and safe therapeutic opportunities for patients with RTT, who currently have limited treatment options. Furthermore, the LAVENDER and LILAC trials revealed the long-term safety and efficacy of trofinetide. Additionally, no severe adverse effects were reported on epilepsy, heart, or bone-related symptoms.[39][40][41] 

Reviews revealed that trofinetide is associated with adverse gastrointestinal events, eg, diarrhea and vomiting, and consequent weight loss. Mild or moderate diarrhea was frequently associated with trofinetide and was responsible for the majority of discontinuations due to TEAEs; however, diarrhea was self-limited and resolved soon after withdrawal of trofinetide.[42] Other limitations include the limited duration of drug supplies, as 1 bottle may last only 3 days, depending on weight, and the relatively high cost per bottle. On the other hand, trofinetide has no direct competitors: single symptoms of the RTT, eg, seizures or aggressive behaviors, are currently treated with drugs that have been developed for patients without the RTT.[43][44][45](A1)

Supportive Therapies

Currently, RTT has no cure, and supportive management aims to provide symptomatic relief through an interprofessional approach. Some of the medical concerns that need to be addressed in patients with RTT include seizure disorders, behavioral alterations, sleep disorders, breathing irregularities, cardiac dysfunction (prolonged QT interval), gastrointestinal dysfunction, and bone fractures.

Gastrointestinal symptoms

Probiotics were studied in patients with RTT who experienced gastrointestinal symptoms and gut microbiota imbalances. The results showed that probiotic L. plantarum PS128 was well tolerated and feasible, with a withdrawal rate of 0% and a retention rate of 100%. Minimal adverse effects, including loose stool, were noted, with significant improvement in dystonia.[46] Digestive problems, eg, gastroesophageal reflux disease (GERD) and constipation, are common in patients with RTT and can be managed with calcium carbonate, histamine H2 receptor blockers (avoiding cimetidine), and increased fiber intake.(A1)

Seizure disorders

Approximately 60% of patients with RTT have some form of seizure disorder. Treatment options to alleviate seizures include valproate, lamotrigine, levetiracetam, carbamazepine, and AEDs. A multicenter study described that generalized tonic-clonic and myoclonic epilepsy were the most typical seizure semiologies, whereas absence and focal epilepsy were less prevalent. Antiseizure medications significantly alter seizure characteristics. The most commonly used antiseizure drugs affecting the severity and frequency of seizures are valproate, levetiracetam, lamotrigine, and clobazam. Reduction of seizures and improvement of cognitive functions were also observed in the ketogenic diet, vagal nerve stimulation, and steroid treatment.[47](B2)

A longitudinal observational study assessed the efficacy and tolerance of cannabidiol (CBD) as adjunctive therapy for RTT patients with epilepsy. Findings revealed a decrease in the incidence of seizures in the majority of the patients. No aggravation of symptoms or adverse effects was noted, except for a case of transient drooling and somnolence episodes at the initiation of CBD. Reduced agitation and anxiety attacks and improved spasticity were also reported. The study concluded that CBD had potential therapeutic value for the treatment of drug-resistant epilepsy, was well tolerated, and, when combined with clobazam, may increase the effectiveness of clobazam alone.[48]

Behavioral and sleep disorders

Behavioral alterations, most often anxiety, can be best addressed with serotonin reuptake inhibitors (SSRIs). Good cariprazine response emphasized the impact of dopamine dysfunction in the complex psychiatric symptoms of RTT.[49]

Patients with RTT often have difficulty initiating sleep and frequent nighttime awakenings, which can be managed with proper sleep hygiene and trazodone once airway obstructions and other causes are ruled out. Breathing irregularities can include apnea, hyperventilation, and breath-holding. Since dysfunction of the autonomic nervous system is a key feature of RTT, heart rate variability has been used to investigate autonomic nervous system dysfunction in RTT during wakefulness. A recent study revealed that the sympathovagal balance shifted towards sympathetic predominance and vagal withdrawal during both wakefulness and sleep in RTT, even when cardiac autonomic dynamics were intact during sleep.[50] 

Respiratory and cardiac disorders

Respiratory issues should be managed at an early stage, regardless of epilepsy onset. Recent literature recommended that noninvasive ventilation is a suitable alternative for patients with RTT, especially those with sleep respiratory disorders and those with hypotonia associated with hypercapnia. Chest physiotherapy should be considered for individuals with difficulty managing the accumulation of respiratory secretions, utilizing airway clearance techniques and devices (eg, PEP mask, AMBU bag, or cough machine), which are more appropriate and tolerated by the patient. The study also emphasized the need for individualized programs to manage scoliosis and the importance of considering gastrostomy in patients at increased risk of aspiration pneumonia.[51][52] Successful management of these irregularities can be complex. Precautions should be taken to avoid medications that alter breathing patterns (eg, opioid medications).(B3)

Cardiac irregularities include a prolonged QT interval, which can be more challenging to manage in patients with RTT than in the general population. Studies in mice with MECP2 mutations suggest that beta-blockers may not be sufficient. Precautions should be taken to avoid medications that further prolong the QT interval (eg, macrolides).

Musculoskeletal disorders

Bone fractures are 4 times more common in patients with RTT compared to the general population, and vitamin D levels should be closely monitored and supplemented as required. Surgical treatment for RTT-associated scoliosis is rare but has increased over 19 years. However, there were reports of higher costs, longer hospital stays, more complications (particularly respiratory), and a higher rate of nonroutine discharge dispositions compared to other patients with neuromuscular scoliosis (NMS).[53]

Another study demonstrated that a 12-week course of low-dose extracorporeal shock wave therapy (ESWT) administered weekly benefits children with RTT by reducing spasticity and enhancing the gross motor function of the lower limbs. Acoustic radiation force impulse sonoelastography demonstrated deterioration in muscle stiffness. This diverse therapeutic response to ESWT may be due to the mutation of MECP2 in patients with RTT, which continuously impacts and drives the pathophysiology differently.[54]

Rehabilitative Therapies

A recent study highlighted that game-based cognitive stimulation elicits substantial EEG changes in patients with RTT, thereby enhancing brain connectivity and information flow, which contribute to improved cognitive functions and increased attention. This is observed during the shift towards higher frequency bands and increased spectral entropy, which is aligned with enhanced brain activation during cognitive sessions. Therefore, these findings serve as markers for evaluating cognitive interventions and propose gaming-related activities as an effective medium for enhancing learning outcomes.[55][56]

Other studies suggest that physical therapy and rehabilitation, including walking training with a treadmill combined with virtual reality, may represent a new strategy for Rett syndrome rehabilitation.[57] On the other hand, studies on speech therapy using alternative and augmentative communication (AAC) have shown that these procedures are effective in teaching various component skills required for expressive communication in patients with complex communication needs. The results of these studies showed that individualized procedures, including behavior chaining, differential reinforcement, and delayed prompting, were effective in teaching page-linking with both high-tech and low-tech AAC devices.[58](B3)

For psychosocial support, a recent study demonstrated an increase in social interaction among patients with RTT when interacting with classmates in a school setting through the use of a low-tech tool, called Click4all, integrated into cognitive and motor training. This is a vital finding, as patients with RTT are typically restricted and isolated.[59] Other treatment options include occupational therapy and psychosocial support for families. Management of these conditions can substantially improve the quality of life of patients with RTT and should not be overlooked.[60][61](B2)

Investigational Therapies

Recently, the CRISPR-Cas9 technology has the potential to impact stem cell therapies for various genetic diseases, eg, RTT, by enabling the correction of genes or mutations in human patient cells. The Magnetic Nanoparticle-Assisted Genome Editing (MAGE) platform significantly improved the transfection efficiency, biocompatibility, and genome-editing accuracy of CRISPR-Cas9 technology.

In one study, the MAGE was applied to correct the mutated MECP2 gene in induced pluripotent stem cell-derived neural progenitor cells (iPSC-NPCs) from patients with RTT. When magnetofection and magnetic-activated cell sorting were combined, MAGE demonstrated higher multiplasmid delivery and repair efficiencies with significantly shorter incubation times than conventional transfection agents, with no size limitations on plasmids. When differentiated into neurons, the repaired iPSC-NPCs revealed the same characteristics as wild-type neurons, further confirming MAGE and its potential for future clinical applications.[62]

Differential Diagnosis

RTT can often be misdiagnosed as other neurological and developmental disorders because it has similar connections with the CNS and other organ systems, particularly in the gut region. Recent reviews have highlighted the connection between the central nervous system (CNS) and gut microbiota, with evidence suggesting bidirectional communication between the CNS and gut through the microbiota-gut-brain axis (MGBA). The gut microbiota affects the CNS by regulating neurogenesis, myelination, glial cell function, synaptic pruning, and blood-brain barrier permeability, with implications in various neurological diseases. Furthermore, the mood of delivery, exercise, psychotropic agents, stress, and neurologic drugs can influence the MGBA. Therefore, understanding the MGBA may be used as a springboard for possible research into microbial-based interventions and proper diagnosis, early detection, prompt intervention, and innovative therapeutic strategies for the following neurological diseases in both children and adults:

• Autism spectrum disorder
• Attention-deficit hyperactivity disorder
• Alzheimer's disease 
• Non-Alzheimer's neurodegeneration and dementia
• Frontotemporal lobe dementia
• Wilson-Konovalov disease
• Multisystem atrophy
• Huntington's chorea
• Parkinson's disease
• Multiple sclerosis
• Amyotrophic lateral sclerosis
• Temporal lobe epilepsy
• Depression
• Schizophrenia
• Cerebral palsy
• Tourette syndrome
• Fetal alcohol spectrum disorders
• Genetic neurodevelopmental disorders (eg, Down, Angelman, and Turner syndromes)
• Nonspecific developmental delay [63][64][65]

Recent studies have also discussed how brain-derived neurotrophic factor (BDNF), expressed during brain development, plays crucial roles in regulating the development and function of the GABAergic system in the cortex and the striatum. The presence of BDNF single-nucleotide polymorphisms and disruptions in BDNF levels alter the excitatory/inhibitory balance in the brain. This imbalance has different effects on the pathogenesis of RTT as compared to other neurodevelopmental diseases like autism spectrum disorder and schizophrenia.[66]

RTT and Fragile X syndrome are 2 monogenetic neurodevelopmental disorders with complex clinical presentations. However, the latter is due to the silencing of the FMR1 gene, which encodes the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein that affects different steps of RNA metabolism and modulates the translation of numerous proteins, eg, a large set of synaptic proteins. Even if they have distinct genetic etiologies, overlapping features are present in RTT and Fragile X syndrome since both MeCP2 and FMRP affect brain activity.[67]

Additionally, patients with RTT may manifest with periodic episodes of gastrointestinal problems, hypoplasia, early-onset osteoporosis, bruxism, and screaming episodes, especially noted in males exhibiting a unique and variable phenotype. Recent case reports described the atypical presentation of RTT that remarkably mimics the clinical features of a genetic metabolic disorder called Bartter syndrome, which includes loss of previously acquired language and motor skills, repetitive hand movements, breathing irregularities, seizures, sporadic episodes of gastrointestinal distress, hypoplasia, early-onset osteoporosis, bruxism, and episodes of screaming. The main difference between Bartter and RTT is an unusual and atypical presentation of RTT in a young male child with a de novo c.806delG hemizygous mutation.[68]

Staging

Staging

Before the RTT criteria revisions and the discovery of MECP2, a staging system was implemented to guide clinicians to track the clinical course of RTT. Its progression has multiple stages, although most phenotypes are related to the nervous system, particularly the brain. Generally, approximately 95% of RTT cases are due to MECP2 gene mutations, an X-linked gene that encodes for MeCP2, a regulator of gene expression.[12] Notably, the following staging system does not predict life expectancy and should not be used for diagnostic purposes:

• Stage 1: This stage begins around 6 to 18 months and involves developmental arrest. Some signs include limited eye contact, deceleration of head growth, nonspecific hand-wringing, and gross motor delays.
• Stage 2: The onset occurs between the ages of 1 and 4, characterized by regression and rapid deterioration. Stage 2 is characterized by stereotypic hand movement (hand-wringing or washing), loss of speech, irritability, and disturbed sleep.
• Stage 3: The onset is between the ages of 2 and 10 and is characterized by improved behavior, communication skills, and hand use.
• Stage 4: The onset of this stage begins after the age of 10 years and is characterized by dystonia, reduced mobility, and bradykinesia.

Prognosis

The life expectancy of an individual with RTT can vary depending on the type of MECP2 mutation inherited.[27] Typically, individuals with RTT survive into middle age, and recent studies suggest they may survive longer.

Recent literature has compared the distribution of MECP2 variants and clinical severity between younger individuals with Classic RTT (those younger than 30 years old) and older individuals (those older than 30 years old). Unexpectedly, the overall severity of clinical features increased from the first to the last visit in the younger cohort, but not in the older cohort. Some specific clinical features in the older cohort remained unchanged from the first to the previous visit, while others showed improvement or worsening. These data demonstrated that clinical features change with increasing age among adults with RTT.[69]

Recent reviews mentioned that pneumonia is the most frequent cause of death for patients with RTT, with a 77.8% survival rate at the age of 25. Typically, patients with RTT survive until their fifth decade, with cardiorespiratory compromise as the leading cause of death.[12] Another study mentioned pneumonia as the leading cause of death due to gastrointestinal dysfunctions, including feeding abnormalities, swallowing dysfunction, and gastrointestinal issues leading to aspiration, which can also cause poor weight gain, oral motor dysfunction, and air swallowing among children with RTT. In this regard, a fiberoptic endoscopic evaluation of swallowing was performed among RTT patients with tongue dyskinesis and a prolonged oral stage. This revealed the following: liquid entering the airway without coughing, with the majority doing well with pureed meals. Age was not correlated with pneumonia episodes, but pureed material was related to pneumonia, whereas liquids were not. All aspiration/penetration was observed before the pharyngeal phase. No patients younger than 7 who experienced pneumonia episodes were identified. Moreover, silent aspiration can occur early in infancy, although pneumonia episodes can occur later.[70]

Another study characterized the long-term nutritional and gastrointestinal course of RTT and found that anthropometric parameters deteriorate with age, regardless of the specific genetic mutation underlying the condition. The study identified common symptoms in patients with RTT, eg, chewing and feeding difficulties, constipation, and gastroesophageal reflux.[71] Furthermore, RTT has a significant negative impact on family functioning. The quality of life in children, as perceived by their parents, is also affected. Counseling families and planning clinical and support management strategies should be considered.[72][73] 

Complications

RTT is associated with multiple complications affecting various organ systems, requiring lifelong interprofessional care. Neurological issues, eg, seizures, cognitive impairment, and motor dysfunction, significantly impact daily living. Breathing irregularities, eg, breath-holding, hyperventilation, and swallowing air, can contribute to discomfort and further complications. Gastrointestinal problems, eg, feeding difficulties, growth restriction, and difficulty chewing, may lead to nutritional deficiencies. Orthopedic issues, eg, scoliosis and abnormal gait patterns, can cause mobility challenges. Sleep disturbances, teeth grinding (bruxism), and autonomic dysfunction further add to the disease burden. Due to its multisystem involvement, RTT management focuses on symptomatic and supportive care. (Please refer to the Treatment section for more information on the complications of RTT).