Vein of Galen malformations
Vein of Galen malformations are congenital arteriovenous malformations involving the deep venous system of the brain that were first described in 1895
Sep. 24, 2021
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Rett syndrome is a rare genetic neurologic disorder of the grey matter of the brain that primarily affects females but has also been found in male patients. The incidence is 0.5 to 1 per 10,000 live female births (141; 67). The clinical features include deceleration of the rate of head growth and a period of regression followed by stagnation or stabilization. Repetitive and stereotyped hand movements, such as wringing, are seen. There is usually loss of expressive language. Those affected with Rett syndrome require multidisciplinary care as many systems can be involved. Up to 80% of individuals with Rett syndrome will have seizures. Scoliosis, growth failure, and constipation are very common and can be problematic.
• Rett syndrome is a neurodevelopmental disorder with an incidence of 0.5 to 1 per 10,000 live female births that contributes significantly to severe intellectual disability in females worldwide.
• Patients with Rett syndrome present with loss of purposeful hand movements, partial or complete loss of expressive language, and stereotypical nonpurposeful hand movements.
• Patients with Rett syndrome usually present with a period of regression followed by some recovery or stabilization.
• Ninety percent of cases of Rett syndrome are secondary to methyl-CpG-binding protein 2 (MECP2) mutations. However, other mutations related to cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1) have been identified.
• Genetic testing has dramatically affected the pattern and timing of diagnosis of Rett syndrome. It has further characterized the phenotype.
• Management of Rett syndrome requires a multi-disciplinary approach as many systems can be involved.
Rett syndrome (OMIM 312750) was identified and published in 1966 by Dr. Andreas Rett, an Austrian physician. In 1954, he first noticed this syndrome in 2 girls as they sat in his waiting room with their mothers. He observed repetitive hand-washing motions. He found similarities when comparing developmental and clinical histories (199).
In 1960, Dr. Bengt Hagberg in Sweden collected clinical records of girls with similar symptoms. In 1983, Dr. Hagberg published findings in the mainstream English journal, Annals of Neurology (105). It was not until the second article about the disorder was published that Rett syndrome was generally recognized. Dr. Hagberg and Dr. Witt-Engerström developed a staging system in evaluation of Rett syndrome in 1986 (107).
The clinical criteria for the diagnosis of Rett syndrome have undergone multiple revisions, with the latest being published in 2010 (170).
In 1999, Zoghbi and her team identified mutations in the X-linked gene, methyl-CpG-binding protein (MECP2) that lead to most cases of Rett syndrome (07).
Children with Rett syndrome share many physical, cognitive, behavioral, and motor characteristics. The current diagnostic criteria are listed below:
Consider diagnosis when postnatal deceleration of head growth is observed.
Required for typical or classic Rett syndrome:
1. A period of regression followed by recovery or stabilization.*
Required for atypical or variant Rett syndrome:
1. A period of regression followed by recovery or stabilization.*
1. Partial or complete loss of acquired purposeful hand skills.
Exclusion criteria for typical Rett syndrome:
1. Brain injury secondary to trauma (peri- or postnatally), neurometabolic disease, or severe infection that causes neurologic problems.***
Supportive criteria for atypical Rett syndrome:##
1. Breathing disturbances when awake.
* Due to the fact that MECP2 mutations are now identified in some individuals prior to any clear evidence of regression, the diagnosis of “possible” Rett syndrome should be given to those individuals under 3 years of age who have not lost any skills but otherwise have clinical features suggestive of Rett syndrome. These individuals should be reassessed every 6 to 12 months for evidence of regression. If regression manifests, the diagnosis should then be changed to definite Rett syndrome. However, if the child does not show any evidence of regression by 5 years, the diagnosis of Rett syndrome should be questioned.
** Loss of acquired language is based on best acquired spoken language skill, not strictly on the acquisition of distinct words or higher language skills. Thus, an individual who had learned to babble but then loses this ability is considered to have a loss of acquired language.
*** There should be clear evidence (neurologic or ophthalmological examination and MRI/CT) that the presumed insult directly resulted in neurologic dysfunction.
# Grossly abnormal to the point that normal milestones (acquiring head control, swallowing, developing social smile) are not met. Mild generalized hypotonia or subtle developmental alterations during the first 6 months of life is common in Rett syndrome and do not constitute an exclusionary criterion.
## If an individual has or has ever had a clinical feature listed it is counted as a supportive criterion. Many of these features have an age dependency, manifesting and becoming more predominant at certain ages. Therefore, the diagnosis of atypical Rett syndrome may be easier for older individuals than for younger. In the case of a younger individual (under 5 years old) who has a period of regression and ≥ 2 main criteria but does not fulfill the requirement of 5/11 supportive criteria, the diagnosis of “probably atypical Rett syndrome” may be given. Individuals who fall into this category should be reassessed as they age and the diagnosis revised accordingly.
Natural history. Girls with classic Rett syndrome are often born at term after an uneventful pregnancy and delivery. Typically, the family and the primary clinician are not concerned about development until after 6 months of life, although it has been recognized that some alterations in initial development can be present in these individuals (58). Deceleration of head growth is often the first sign of Rett syndrome. This can occur as early as 2 to 3 months but is not present in all individuals with Rett syndrome and has been removed from the diagnostic criteria. Affected patients initially develop normally and then experience loss of speech and purposeful hand use and onset of stereotypic midline hand movements and gait abnormalities. Following the regression phase, there is a period of recovery of nonverbal communication and interaction with the environment. Epilepsy, disorganized breathing, and autonomic dysfunction also occur in the majority of patients.
A staging system was described to explain the clinical course of Rett syndrome (107). With the advent of genetic testing, this is no longer in widespread clinical use. However, it can be helpful in providing anticipatory guidance to parents.
Stage 1 is when decreased head growth velocity is first noticed. Girls will also be hypotonic and experience gross motor delays. Typically, this is also the time when there is less eye contact, social interaction, and use of toys as well as the onset of loss of hand skills. This stage occurs between 6 and 18 months of life and may last for many months.
Stage 2 is the period of regression, and the deterioration is quite rapid. Midline hand stereotypies, such as hand-wringing or -washing, and periodic breathing abnormalities are seen. Periods of inconsolable, unprovoked crying and irritability are not uncommon. Autistic features emerge as decreased head growth continues. This stage has onset between 1 and 4 years, may be acute or insidious, and typically lasts weeks to months.
Stage 3 is a plateau phase. Improvements in behavior, hand use, and communication skills are seen. This is the stage when “eye pointing” becomes apparent. Epilepsy is prominent during this stage, along with the beginnings of motor dysfunction. It will begin between 2 and 10 years and may last for many years, with some girls never progressing to stage 4.
Stage 4 is characterized by decreased mobility. Some girls will become wheelchair-dependent whereas others will remain ambulatory well into adulthood. Communication may continue to improve, but language will not be regained. Cognitive function is stable, staring may begin, and epilepsy improves. Spasticity, dystonia, hypomimia, and bradykinesia are usually seen. Scoliosis and quadriparesis may also occur in this stage. This stage usually begins after the age of 10 years.
Communicative behavior. Loss of fine motor skills and communicative behavior is often seen after deceleration of head growth, between 12 to 18 months of age (105; 104). The rate of regression can vary, from rapid loss of language to slow and insidious loss of motor skills over weeks to months. During the phase of regression, impaired sleep will begin, with episodes of inconsolable screaming that begin abruptly and can last for hours. The regression period is also when stereotyped hand movements present. They may initially be subtle and interspersed with purposeful hand use. Stereotypies are often midline and may include opposition of hands, finger kneading and rubbing, and hand-clapping as well as hand-washing, -wringing, -squeezing, -twisting, and pill rolling (235). In atypical Rett syndrome, hair pulling, bruxism, retropulsion, and protrusion of lips is commonly seen (36). Each affected individual will develop her own hand pattern.
The regression phase will be followed by a period of recovery, where eye contact will improve nonverbal communication, and nonverbal interactions with the environment will also improve. Some girls will retain 1-word expressions, although the majority will lose expressive language. They may maintain the ability to communicate using gaze, body language, and facial expression. Standardized instruments have difficulty assessing these behaviors and systematic reviews suggest evidence of communicative behaviors, with the validity of the findings being unknown (51).
Epilepsy. Seizures occur in the majority of patients, with rates ranging from 50% to 90%. Seizure onset is usually toward the end of the regression period or after the regression period (87). In patients with loss of function of MECP2, a possible mechanism for epilepsy is impaired excitatory inhibitory balance onto CA3 pyramidal neurons, leading to a hyperactive hippocampal network (29). The most common types of seizures are tonic-clonic, tonic, myoclonic, and focal seizures with impaired awareness.
Continuous spike and wave in slow-wave sleep has been described in Rett syndrome, and when identified, it should be treated to optimize development (17). The occurrence of epilepsy in Rett syndrome may be overestimated because affected patients have a variety of abnormal behaviors that can be mistaken as seizure manifestations (52). 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 EEG changes.
The prevalence of epilepsy increases with age. Between 2 and 4 years, prevalence is approximately 33%; between 5 and 9 years prevalence is 60%; between 10 and 14 years, prevalence is 77%; between 15 and 29 years, prevalence is greater than 84%; and 30 years and older prevalence is 86%. The frequency of seizures varies from every 6 months to daily (87). One study found that two thirds of women above 30 years of age remained with active epilepsy, and 50% of them had seizures at least weekly (114). Clinicians should consider Rett syndrome or atypical Rett syndrome and genetic testing in those with epilepsy with some clinical features overlapping with Rett syndrome (180).
Extrapyramidal signs. Additionally, girls with Rett syndrome will often have extrapyramidal disturbances, including bruxism (97%), excessive drooling (75%) oculogyric crises (63%), hypomimia (63%), dystonia (59%), rigidity (44%), bradykinesia (41%), and proximal myoclonus (34%) (70). It has been shown that MECP2 regulates a unique set of genes critical for modulating motor output of the striatum, and that aberrant structure and function of the striatum due to MECP2 deficiency may underlie the motor deficits in Rett syndrome (126).
Growth. By age 2 years, the mean head circumference is 2 standard deviations below the mean. Deceleration of weight and height measurements will follow, with mean weight below normal at 13 months of life and continuing to decline, plotting to the second percentile by age 13 years. Mean height is noted to be below normal by 18 months and is 2 standard deviations below the norm by 12 years.
There have been 5 different growth patterns noted in typical Rett syndrome: severe somatic growth failure with microcephaly (33%), moderate somatic growth failure with microcephaly (19%), normal somatic growth with microcephaly (30%), normal growth (14%), and moderate somatic growth failure with normal head circumference (3%). Approximately 8% of girls with Rett syndrome will have somatic growth above the 98th percentile. A greater proportion of girls with atypical Rett syndrome will have normal growth (233).
Musculoskeletal features. Typically, the gait of affected individuals is broad-based and ataxic. There is often retropulsion as well as repetitive rocking back and forth. Transitioning between floor surfaces or colors is often difficult.
As patients grow older, scoliosis may become apparent, reported in 53% to 75% of individuals. Factors associated with scoliosis include delayed, lost, or absent walking and constipation. The risk may vary with genotype, being found to be decreased in both the R294S and R306C mutations of MECP2 (Ager et al 2006; 188).
Individuals with Rett syndrome experience nearly 4 times the amount of fractures as the general population (53). This is attributed to low bone mineral density (103).
Feeding and nutrition. Although interactions with the environment may improve, girls will frequently experience feeding impairment, seen as chewing or swallowing difficulties, choking, and nasal regurgitation (163). The upper gastrointestinal tract may also be affected with oropharyngeal dysfunction, including reduced oropharyngeal clearance, laryngeal penetration of liquids and solid foods during swallowing, and upper gastrointestinal dysmotility. Aggressive nutritional support improves growth in Rett syndrome, with gastrostomy tubes showing increased velocities for both height and weight.
Cardiac and autonomic dysfunction. The annual incidence of sudden, unexpected death is higher in Rett syndrome than in the general population (0.3%, vs. 0.0001% for people ages one to 22 years). It is thought that abnormal autonomic nervous system regulation causes increased incidence of a prolonged QT interval (216; 62; 99).
Approximately 50% to 70% of patients with Rett syndrome have clinical features that indicate autonomic nervous system dysfunction with increased sympathetic tone. These include the presence of cold blue feet, hands, or both; drooling; and breathing irregularities. A deficiency in substance P in the central nervous system identified in girls with Rett syndrome may contribute to impairment of autonomic nervous system function, resulting in cardiac dysautonomia as well as gut dysmotility (45; 46). Patients with Rett syndrome often have altered pain sensitivity. One study showed that the MECP2 gene plays an analgesic role in both acute pain transduction and chronic pain formation through regulating CREB-miR-132 pathway (274).
Respiratory control and sleep. A characteristic pattern of disordered breathing during wakefulness occurs in 60% to 77% of patients with Rett syndrome (83; 224). This pattern consists of episodes of hyperventilation with concomitant hypocapnia alternating with hypoventilation or apnea. The periods of hypoventilation or apnea may last as long as 20 to 120 seconds and result in hypoxemia. Breathing usually is normal between these episodes.
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 may 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. A case report of subcutaneous emphysema has been attributed to aerophagia due to hyperventilation in Rett (39).
Sleep disturbances affect at least 80% of patients with Rett syndrome (266). Girls with Rett syndrome have poor sleep quality with alterations in slow wave and REM sleep stages. Obstructive respiratory events are uncommon in patients without adenotonsillar hypertrophy. Central respiratory events are rare (06). The symptoms most commonly reported are irregular sleep times, shortened nighttime sleep with increased sleep during the day, and periodic nighttime awakening with laughing, crying, and screaming. One study showed that the p.Arg294 mutation in younger patients is associated with greater disturbances in initiating and maintaining sleep (23).
Defined variants. There are 3 recognized variants of Rett syndrome, and the genotype-phenotype correlation is distinct.
The congenital, or Rolando variant is distinguished by clinical onset within the first 6 months of life (203). Girls are floppy and delayed from the very first months of life (08). The EEG features are similar to those found in classic Rett syndrome. MRI shows corpus callosum atrophy. At approximately 3 months, abnormal head growth is noted. Patients have been noted to weep inconsolably, gain very late head control, if any, and be unresponsive to voice. It is caused by the forkhead box protein G1 (FOXG1) gene mutation. FOXG1 encodes the forkhead box protein G1, which is a transcriptional factor with expression limited to fetal and adult brain tissue and testes.
The early onset seizure, or Hanefeld, variant is characterized by onset of seizures within the first week through 5 months of life amongst typical Rett-like features (109). Hanefeld described a girl who presented with infantile spasms and hypsarrhythmia on EEG prior to the age of one. She went on to develop a progressive encephalopathy characterized by dementia, stereotyped movements, ataxia, and microcephaly. The variant was later extended to include those with seizures before onset of regression (96). The spectrum of phenotypes includes the following: patients with some of the diagnostic criteria of Rett syndrome early onset seizure variant, patients characterized by severe encephalopathy with refractory seizures, patients with X-linked infantile spasms, and patients with autistic features (reduced social interaction with poor eye fixation and avoidance of eye contact and stereotypies) (125; 64). Medical attention is first sought for seizures within the first 3 months of life, and these patients have been noted to be severely hypotonic at that stage (10). None of these patients have the period of apparently normal development, and in fact, some continue to regress after 6 months, unrelated to the epileptic encephalopathy. Brain MRI can show areas of high signal intensity in the white matter or dentate nuclei. The cyclin-dependent kinase-like 5 (CDKL5) gene causes this variation.
The preserved speech, or Zappella, variant is the least severe form. Females with the preserved speech variant show some of the features of classical Rett syndrome, such as midline hand-wringing, but usually will show no general growth failure or head deceleration (155). Epilepsy and hyperventilation are also rare, and after the initial regression, these individuals show improvement in hand use. Language may not be lost at all, and if it is, it can be regained. Lexicon size and syntactic complexity are reported to increase slowly but are usually accompanied by features such as echolalia, peculiar prosody, or limited pragmatic functions. Usually babbling is established by no later than 10 months, but observational studies have reported this is significantly delayed in the preserved speech variant. Also observed are atypical vocalizations, such as inspiratory vocalizations, pressured vocalizations, and high-pitched crying-like vocalizations. These girls will express the pathogenic MECP2 mutation.
Rett syndrome in males. There are 3 main phenotypes seen in males: severe encephalopathy with neonatal fatality, classic Rett syndrome, and mild neuropsychiatric phenotypes (254; 40; 79; 239; 32; 213).
Male siblings of female Rett syndrome patients with identical MECP2 mutations develop a severe encephalopathy, including epilepsy, hypotonia, dyskinetic movements, and central hypoventilation with apnea. They are often noted to have a distinct salt-and-pepper hair color and die by 1 to 2 years of age. Postmortem examinations will demonstrate malformed cortex in the deep insular gyri and part of the postcentral, superior parietal, inferior parietal, and superior temporal gyri of the perisylvian area. Microscopic examination reveals polymicrogyria with extensive fusion of the molecular layers in this area.
The majority of males with a Rett syndrome-like phenotype do not express the MECP2 mutation, or they express it with somatic mosaicism. Klinefelter syndrome (46 XXY) allows phenotypic males to replicate the somatic mosaicism achieved by females and avoid neonatal fatality. There is a wide spectrum of neurologic phenotypes in MECP2 mutations resulting in X-linked mental retardation, ranging from mild to severe. A male with classic Rett syndrome has been reported, with a mutation in MeCP2 exon 1 (238)
Cardiac. Prolonged QT values has been found to be associated with Rett syndrome (216; 62). Certain medications can exacerbate arrhythmias in these children. These include, prokinetic agents, antipsychotics (such as thioridazine), tricyclic anti-depressants, anti-arrhythmics (such as quinidine, sotalol, amiodarone), anesthetic agents (such as thiopental, succinylcholine), and antibiotics (such as erythromycin, ketoconazole.) These should, therefore, be avoided because of the possibility of precipitating electrocardiogram QT abnormalities and cardiac arrhythmias.
Increased tone or contractures. Children with Rett syndrome can develop increased tone, often manifesting as tight heel cords, toe walking, contractures, and decreased ambulation. Some may also develop dystonic spasms. Early physiotherapy and occupational therapy consults are important to prevent complications (25). Children may require medications for neuropathic pain, such as gabapentin, and specific medications for movement disorders and rigidity, such as benzodiazepines, trihexyphenidyl, baclofen, and carbidopa-levodopa. If contractures develop, orthoses or surgical intervention may be required (110; 25).
Poor weight gain. Girls with Rett syndrome can have poor weight gain and failure to thrive (26). This is secondary to multiple reasons, such as swallowing difficulties, impaired chewing, or increased energy expenditure. Swallowing assessments and consultations with gastrointestinal specialists and dietitians can optimize a child’s nutrition and growth.
Sleep disorders. There can be several reasons for impaired sleep in Rett syndrome, including primary sleep disorders and seizures. If there is clinical suspicion of sleep disorder, polysomnography or prolonged video-EEG monitoring may be necessary for proper diagnosis and management.
Symptomatic scoliosis. Scoliosis is seen in a high percentage of girls, up to 65% (256). Proper monitoring of the scoliosis and referral to an orthopedic specialist may be necessary to prevent further complications.
Osteoporosis. Clinicians should be aware that osteoporosis is common in Rett syndrome. Children may present with fractures. Proper nutrition and maintaining muscle use and strength is important. It can be treated with vitamin D, phosphorous, and calcium. Some children are treated with medications such as alendronate or intravenous pamidronate. Teriparatide, a recombinant form of parathyroid hormone, was shown effective in the management of osteoporotic fractures in one subject with Rett syndrome (28).
An eight-month-old girl was referred by her primary care doctor to a pediatric neurologist for evaluation of developmental delay. Following an uncomplicated pregnancy, she was born by caesarian section secondary to breech presentation. The girl's parents first had concerns at 3 months of age when the patient was less attentive and less interactive than other children her age. She was floppy and demonstrated tongue thrusting. At eight months, she was just starting to roll over. The remainder of her past medical history and family history were unremarkable. Head circumference was at the second percentile. No dysmorphic features were noted, and neurologic examination was significant for hypotonia and mild hyperreflexia. Development was noted to be at the 3- to 4-month level.
By 18 months, the child had developed seizures. The most frequent seizure type was atypical absence seizures, but she also had atonic seizures and generalized tonic-clonic seizures. An MRI of the brain was normal. Genetic testing was pursued at this point and showed MECP2 deletion on chromosome X28. The girl was lost to follow-up but returned at 4 years of age. At that time, she had an ataxic gait and had been prescribed ankle-foot orthoses. She had not developed any verbal expressive language and did not have any purposeful hand movements. She was not sleeping well and was experiencing night terrors and was referred to a sleep specialist. Seizures were well controlled on a combination of valproic acid and lamotrigine.
By early adolescence, the girl had developed aggressive behaviors and behavioral psychologists were consulted for management. She developed paroxysmal posturing of her hands. Her parents were concerned about seizures. At that time, she was admitted for video-EEG monitoring to characterize the events, and they were found to be nonepileptic in nature. The diagnosis of dystonic posturing was confirmed, and she responded well to low-dose benzodiazepines. Her seizures remained well controlled. As adolescence progressed, scoliosis developed, and surgery was performed.
MECP2 gene. It is well established that mutations in MECP2, located on Xq28, account for 95% of typical Rett and 73.2% of atypical Rett syndrome (57).
More than 99% of female Rett syndrome incidences are de novo mutations in the MECP2 gene or possibly from a parent who has germline mosaicism. Approximately 600 mutations have been detected so far within the MECP2 gene (37; 38). Rarely, a MECP2 mutation may be inherited from a carrier mother in whom favorable skewing of X-chromosome inactivation results in minimal to no clinical findings. When the mother is a known carrier, the risk to her offspring of inheriting the MECP2 mutation is 50%.
MECP2 mutations are nearly always lethal in males. In the rare surviving males with MECP2 mutations, phenotypes differ from classical Rett syndrome. The most common clinical presentation is the severe neonatal-onset encephalopathy with microcephaly (255). Males have classical Rett syndrome when the mutation arises as somatic mosaicism or when they have an extra X chromosome. A review looked at Rett syndrome in male subjects. Mutations of the MECP2 gene were present in 56% of cases, and 68% of cases reported other genetic abnormalities (198). A de novo missense mutation in exon 3 of the MECP2 gene (P225L) has been found in a male with severe mental retardation, spastic tetraplegia, dystonia, apraxia, and neurogenic scoliosis (162). Duplication and triplication of the MECP2 gene have also been identified as the genetic cause of the MECP2 duplication syndrome in males (32).
MECP2 mutations may also be found in families exhibiting X-linked intellectual disability, including manic-depressive psychosis, pyramidal signs, parkinsonian features, and macroorchidism, also known as PPM-X Syndrome (131).
The primary genetic pathological change of Rett syndrome is the mutations in the MECP2 gene, an X-linked gene that spans 76 kb in the long arm of the X-chromosome (Xq28). Advances in knowledge of the MECP2 gene, including functional roles and its mechanisms of action, have enhanced its relevance in the pathobiology of Rett syndrome. The connection of MECP2 with Rett syndrome might be related to its direct or indirect involvement in gene expression regulation. The following paragraphs will discuss the structure, expression, function, and relationship of MECP2 genotype and phenotype.
Rett syndrome is diagnosed also in 3% to 5% patients who are negative for MECP2 mutations (169). CDKL5 and FOXG1 are other genes identified as causative genes in atypical forms of Rett syndrome (257; 08).
CDKL5 /Cyclin-dependent kinase-like 5. The first reports that mutations in CDKL5 were associated with Rett syndrome were published in 2004 (232). Common clinical characteristics include early onset seizures (typically by 3 months of age), severe intellectual disability, and gross motor impairment.
In addition, a broad forehead, deep-set eyes, well-defined philtrum, tapered fingers, and full lips have been described (68). A comprehensive phenotypic assessment of a large cohort of patients with CDKL5 mutations has been published with the aim of determining whether these patients actually fall under the spectrum of Rett syndrome (68). The study by Fehr and colleagues demonstrated that almost 25% of their cohort of 86 patients with mutations in CDKL5 did not meet the Neul criteria for the early onset seizure variant of Rett syndrome. Thus, the authors proposed that patients with mutations in CDKL5 should be considered a separate entity to Rett syndrome, rather than be a variant form of the disorder, and suggested it should be known as the CDKL5 disorder.
FOXG1/Forkhead box protein G1. A small number of patients diagnosed with Rett syndrome have mutations in the FOXG1 gene and are diagnosed with the congenital variant of Rett syndrome. FOXG1 encodes a winged-helix transcriptional repressor with expression restricted to testis and brain. It is critical for forebrain development. Point mutations or truncating mutations in FOXG1 have been reported (190; 134). FOXG1 localizes to mitochondria and coordinates cell differentiation and bioenergetics (183). Patients with mutations in FOXG1 have been reported to have brain malformations, especially hypoplasia of the corpus callous (273; 113).
To date, 59 patients have been reported with pathogenic FOXG1 mutations (36 female and 23 male) with only 27 being diagnosed with atypical Rett (20 female and 7 male) (133). However, as was the case for CDKL5 mutations, there are features that are seen commonly in those with FOXG1 mutations, such as agenesis or hypoplasia of the corpus callosum, that have not been reported in individuals with MECP2 or CDKL5 mutations, and consequently, it has been suggested that mutations in FOXG1 cause a clinical entity distinct from Rett syndrome (195).
MEF2C/Myocyte Enhancer Factor 2C. The involvement of MEF2C in Rett syndrome was first reported in 2008 (146). It has subsequently been estimated that around 2% of those with a Rett-like phenotype are caused by mutations in MEF2C (278; 139). MEF2C haplo-insufficiency syndrome, a disorder resulting from the microdeletion of the 5q14.3 region, has been shown to exclusively affect neuronal function, with affected individuals having severe intellectual disability, seizures, hypotonia, and cerebral malformations (278).The prevalence of stereotypic hand movements in MEF2C syndrome is significant, prompting the suggestion that this disorder overlaps with Rett syndrome (139). Of note, patients with MEF2C mutations also show reduced MECP2 and CDKL5 expression (278). This phenotypic and genotypic connection has raised the possibility of a common pathway or a convergence in separate pathways involving MECP2, CDKL5, and MEF2C, which may be impaired when any of these genes are dysfunctional.
Other Genes. The advent of whole-exome sequencing in the identification of novel disease-causing genes has been rapid and the subsequent results within Rett research has been notable with numerous genes being investigated for their disease-causing potential. See Table 2.
(Glissen et al 2014; 119)
ANKRD31, CHRNA5, HCN1, SCN1A, TCF4, GRIN2B, SLC6A1, MGRN1, BTBD9, SEMA6B, AGAP6, MGRN1, VASH2, ZNF620, GRAMD1A, GABBR2, ATP8B1, HAP1, PDLIM7, SRRM3, CACNA1I
TCF4, EEF1A2, STXBP1, ZNF238, SLC35A2, ZFX, SHROOM4, EIF2B2, RHOBTB2, SMARCA1, GABBR2, EIF4G1, HTT
PWP2, SCG2, IZUMO4, XAB2, ZSCAN12, IQSEC2, FAM151A, SYNE2, SMC1A, ARHGEF10L, HDAC1, TAF1B, KCNJ10, CHD4, LRRC40, LAMB2, GRIN2B, IMPDH2, SAFB2, ACTL6B, STXBP1, TRRAP, WDR45, SLC39A13, FAT13, IQGAP3, NCOR2, GABRB2, TCF4, GRIN2A
GRIN2B, GABBR2, MEF2C, STXBP1, KCNQ2, SLC2A1, TCF4, SCN2A, SYNGAP1, CACNA1I, CHRNA5, HCN1
ATP6V0A1, USP8, MAST3, NCOR2
MECP2 gene and structure. The MECP2 gene is located in between the interleukin-1 receptor associated kinase gene (IRAK1) and the Red Opsin gene (RCP). MECP2 comprises 4 major exons (exon 1-4) and 3 introns (intron 1-3). MECP2 protein is part of the methyl-CpG binding protein family and is composed of 5 major domains, N-terminal domain (NTD), methyl binding domain (MBD), inter-domain (ID), transcription repression domain (TRD) and C-terminal domain (CTD) (111). MECP2 has 2 different isoforms (MECP2-e1 and MECP2-e2). Even though the isoforms have different expression patterns, they are considered to be functionally equivalent (121). A unique double mutation (c.695G> T; c.880C> T) has been reported to affect the transcription repression domain of MeCP2 and produce a severe clinical phenotype of Rett (81).
MECP2 structure and function might be modulated through post-translational modifications, such as phosphorylation, acetylation, methylation, and ubiquitination. The multiple post-translational modifications of MECP2 play an important role in the complexities of MECP2 transcriptional modulation, which will be discussed in the following sections (94; 56).
MECP2 expression. MECP2 is ubiquitously expressed in many organs. It is predominantly expressed in the brain, lung, and spleen but is also expressed in the liver, heart, kidney, and small intestines (217). Within the brain, the distribution and levels of MECP2 are different, specifically, in the olfactory bulb, cortex, striatum, hippocampus, thalamus, cerebellum, and brainstem. Among the studied brain regions, the highest MECP2 expression is in the cortex and cerebellum (270; 179).
In mouse models, the expression levels of MECP2 in different brain regions correlates with impaired behavioral phenotypes (262). Loss of MECP2 expression in the neurons in the basolateral amygdala causes increased anxiety-like behavior and impaired cue-dependent fear learning (03; 264). A lack of MECP2 expression in the forebrain is associated with abnormal social behaviors, anxiety, and autistic features (80; 34). Decreased expression in hypothalamic neurons results in abnormal physiological stress response, hyper-aggressiveness, and obesity (74).
In the hippocampus of Rett syndrome subjects, excitatory synapses have been demonstrated to be stronger due to altered synaptic trafficking of AMPA-type glutamate receptors. This may lead to deficits in long-term potentiation at central excitatory synapses and contribute to cognitive impairments and epilepsy in Rett syndrome (147).
In the striatum, MECP2 regulates a unique set of genes critical for modulating motor output, and that aberrant structure and function of the striatum due to MECP2 deficiency may underlie the motor deficits in Rett syndrome (126).
Other than neurons, MECP2 expression has also been demonstrated in astrocytes, oligodendrocytes, and microglia (12; 197; 50; 270; 179). Some examples of the impact of MECP2 expression on these cells are listed below.
Macrophages in MECP2-deficient mice are abnormal in number, as well as in glucocorticoid, hypoxia, and inflammatory responses (214). One study showed how MECP2 regulates bioenergetic pathways in microglia. MECP2 was a microglia-specific transcriptional repressor of SNAT1, a major glutamate transporter. This led to reduced microglia, proliferation of mitochondria and production of reactive oxygen species, and increased oxygen consumption, but decreased ATP production and overproduction of glutamate. There may be a therapeutic potential of mitochondria-targeted antioxidants for Rett syndrome (123).
Astrocytes have been shown to have impaired carbon dioxide sensitivity in a mouse model of Rett syndrome. This finding contributes to the understanding of respiratory dysfunction in Rett syndrome and also demonstrates the important role played by astrocytes in central respiratory carbon dioxide (243).
Modulator of transcription. MECP2 is originally considered a transcriptional repressor to silence methylated genes. MECP2 binds tightly to chromosomes in a methylation-dependent manner. The transcription repression domain associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases (168).
In addition, studies show that MECP2 is also a transcriptional activator of expression. MECP2 binds to gene promoters, and associates with the transcriptional activator complexes containing cAMP response element-binding protein. This suggests that MECP2 regulates the expression of a wide range of genes in different brain subregions. Therefore, MECP2 is a modulator of transcription that can both activate or repress target genes (31).
Controlling chromatin structure. MECP2 binding is also associated with nuclear organization. This indicates that its gene regulatory function is context-dependent. MECP2, which localizes to the chromocenters, is a key protein for chromatin architecture. MECP2 mutations have been shown to disrupt the formation of higher-order chromatin structures (172; 11; 157). MECP2 deficiency causes aberrant spindle geometry, prolonged mitosis, and defects in microtubule nucleation (15).
Cytoskeleton function. Studying rats with MECP2 mutations has revealed hypersensitivity to pressure and cold, but hyposensitivity to heat. This has been attributed to dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Eight key genes have been identified that control actin signaling and adhesion formation, and knockdown of these genes in rate prevented sensory hyperinnervation and reversed mechanical hypersensitivity (19).
Role in RNA splicing. Studies imply that MECP2 also plays a role in RNA splicing. Changes in alternative splicing of genes and the interactions of MECP2 with an RNA binding protein have been observed in a mouse model of Rett syndrome (267). Rett syndrome-causing truncating mutations disrupt the interaction between MECP2 and spliceosome complex containing pre–mRNA processing factor 3 (PRPF3) (149). The DNA methylation-dependent binding of MECP2 to exonic sequences modulates alternative splicing to enhance exon recognition (158).
Regulation of the expression of microRNAs. The most recently described function of MECP2 is the regulation of the expression of microRNAs (miRNAs). MicroRNA-137 (miR-137) is one such miRNA, which is involved in regulating neural stem cell proliferation and differentiation (229). The role of MECP2 in regulating miRNA and its contribution to Rett syndrome pathology have been demonstrated in mouse models of Rett syndrome (246). The combined action of RNA-binding protein PUM1 and pluripotent-specific miRNA destabilize MECP2 3’ UTR to differentially modulate MECP2 in in vitro differentiation of human embryonic stem cells into cortical neurons (202).
Biological functions of MECP2. Within neurons, MECP2 plays critical roles in neuronal maturation, terminal neuronal differentiation, modulation of neuronal morphology, synaptic plasticity (196; 276), and in regulation of the microtubule dependent vesicle transport (47).
Oxidative balance. MECP2 loss of function may be involved in oxidative brain damage. The presence of a systemic oxidative stress has been demonstrated in animal studies and Rett syndrome patients with a strong correlation with the patients' clinical status. The restoration of MECP2 function in astrocytes has been shown to improve the developmental outcome of MECP2-null mice. Reexpression of the MECP2 gene in the brain of null mice restored oxidative damage (69). It is suggestive that oxidative damage may be secondary to the role of MECP2 in bioenergetic pathways in microglia (123).
Autoimmune. There is increasing evidence of the relationship between MECP2 and an immune dysfunction, with, apparently, a link between MECP2 gene polymorphisms and autoimmune diseases, including primary Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis. However, further research is needed to better understand this. Antineuronal antibodies and high levels of anti-N-glucosylation (N-Glc) IgM serum autoantibodies have been detected in a statistically significant number of Rett syndrome patients (42).
Oncogene MECP2 is a commonly amplified oncogene in human malignancies with a unique epigenetic mechanism of action. Neupane and colleagues reported that MECP2 is significantly amplified across 18% of cancers. Many cancer cell lines have amplified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 binding to the epigenetic modification 5hmC is required for efficient transformation (171). MeCP2 overexpression has been found to suppress glioma progression by modulating ERK (218).
Cognition. A study that examined MeCP2 function in the adult mouse hippocampus showed that MeCP2 is necessary for memory consolidation (100). This provides insight into the cognitive function of patients with Rett.
Mutations identified. The well-known de novo mutations in the MECP2 mutations that cause disorders in females include classic Rett syndrome, variant Rett syndrome, and patients with mild learning difficulties. Approximately 600 mutations have been detected so far within the MECP2 gene (37; 38). These mutations include missense, nonsense, and silent mutations. Other mutations include: 5’ UTR and 3’ UTR variations, intronic variations, insertions (frameshift, in-frame), and deletions (exonic deletions, frameshift, in-frame) (RettBASE: http://MECP2.chw.edu.au), and pericentric X-chromosome inversion.
The type of MECP2 mutation, its location, and the presence of skewed X-chromosome inactivation modulate Rett syndrome phenotype (257). For example, mutations of the MECP2 C-terminus are associated with hypotonia, profound intellectual impairment, and seizures (205). Almost half of the known disease-causing missense mutations in MECP2-related disorders affect the methyl binding domain (MBD) to disrupt binding to methylated DNA (111). Less frequent mutations are in other domains of MECP2, such as in the extreme C-terminal region of the TRD, CTD, NTD, and ID (153). These domains facilitate MBD-dependent DNA binding (82).
With advances in genetic testing, several new mutations have been found in MECP2. The following are some examples of new MECP2 mutations. A de novo, heterozygous c.489G>A mutation at exon 4 of the MECP2 gene was found in one patient (101). Another patient with Rett syndrome has been shown to have a c.1160C>T (P387L) in exon 4 of the MECP2 gene homozygously. Females with Rett syndrome are usually heterozygous for a mutation in MECP2 (16). Three patients have been shown to share the same novel heterozygous point mutation c.175G>C (p.A59P). This mutation was located in a conserved amino acid in the N-terminal segment of MECP2 (129).
Molecular basis of Rett syndrome. The associated specific molecular pathways of Rett syndrome and how it is related to phenotype is unclear. It is likely that the binding of MECP2 to both specific sequences and epigenetic signatures of DNA affects its molecular activities and post-translational modifications (14).
Studies are aimed at the discovery of specific genes target pathway to expand understanding of phenotypes and to explore future therapeutic methods. Several hypotheses of MECP2 target pathways are discussed here.
MECP2 and epigenetic mechanisms. Patients carrying the single missense mutation in the MECP2 MBD-R133C are generally characterized by a milder form of Rett syndrome, with a delayed onset of regression and preservation of some speech and motor skills (13). The single missense mutation influences the binding properties of the methyl binding domain. It has been demonstrated that the R133C mutation inhibits the binding to major 5-hydroxymethylcytosine (5hmC). 5hmC represents a epigenetic signal. It is hypothesized that 5hmC and MECP2 together play a role in cell-specific epigenetic mechanisms for regulation of chromatin structure and gene expression (159).
MECP2 truncating mutations. Data from normal male patients with truncating mutations between amino acids R270 and G273, located in the middle of the transcription repression domain, appear to differently influence the onset of symptoms and the severity of the syndrome. The first truncation at R270 correlates with neonatal encephalopathy and death. The second at G273 is characterized by significantly longer survival (253). In 2 mouse models expressing either MECP2-R270 or MECP2-G273, it is shown that MECP2 contains 3 AT hook-like domains. One of the 3 is disrupted in MECP2-R270, which impairs its DNA binding and chromatin compaction capabilities. Absence of the AT hook domain leads to altered chromatin structure with loss of alpha-thalassemia or mental retardation syndrome X-linked protein (ATRX). This protein is localized at pericentric heterochromatin (11).
Eukaryotic initiation factor signaling and Rett syndrome. Eukaryotic initiation factor (EIF) signaling is of particular interest in Rett syndrome and autism spectrum disorder as it mediates insulin activity. The lack of repression in MECP2-null mice or in mutant Rett syndrome patients leads to overexpression of insulin-like growth factor binding protein 3 (IGFBP3). Higher levels of IGFBP3 could delay full development of the brain. In fact, growth factor triggered responses and insulin-like growth factor-1 (IGF-1) treatment has been proposed as a promising pharmaceutical approach for Rett syndrome patients to bind the promoter of IGFBP3 (120).
Brain derived neurotrophic factor (BDNF). BDNF is a molecule that has shown to have a role in neuronal survival and synaptic plasticity. MECP2 regulates the expression of the BDNF gene (140). Low levels of BDNF have been found in those with Rett syndrome (48).
CREB signaling. CREB signaling in MECP2 has been shown to decrease the severity of behavioral deficits in mouse models. There is also a significant reduction in the level of CREB in forebrain neurons differentiated from MECP2, MECP2-KO, and V247fs human embryonic stem cell lines (24).
Cytoskeletal genes. Studies have been carried out to investigate cytoskeleton-related genes in brain tissue of Rett syndrome. Decreased levels of Tubulin, alpha 1b (TUBA1B) and Tubulin alpha 3 (TUBA3) have been shown (02). Cells from MECP2-deficient cells also show reduced levels of acetylated α-tubulin. There is a study suggesting that reduced levels of tubulin acetylation can be restored using histone deacetylase 6 (HDAC6) (92).
mTOR signaling and Rett syndrome. A relationship between the mammalian target of the rapamycin (mTOR) signaling and Rett syndrome has been proposed (200). Protein synthesis regulation via mTOR pathway is crucial for synaptic organization, and its disruption is involved in a number of neurodevelopmental diseases. This mTOR pathway is responsible for the altered translational control in MECP2 mutant neurons. This may provide a future therapeutic intervention to modulate protein synthesis and, therefore, restrain the development of Rett syndrome (14). In MECP2-deficient neurons, nucleoli structures are compromised. Nucleoli are sites of active ribosomal RNA (rRNA) transcription and maturation, a process mainly controlled by nucleolin and mechanistic target of rapamycin mTOR-P70S6K signaling. It has been unclear how nucleolin-rRNA-mTOR-P70S6K signaling from Rett syndrome cellular model systems translates into human Rett syndrome brain. One study observed compromised mTOR-P70S6K signaling in the human Rett brain, a molecular pathway that is upstream of rRNA-nucleolin molecular conduits (178). Rett syndrome patients showed significantly higher phosphorylation of active mTORC1 or mTORC2 complexes compared to age- and sex-matched controls. Correlational analysis of mTORC1/2-P70S6K signaling pathway identified multiple points of deviation from the control tissues that may result in abnormal ribosome biogenesis in a Rett syndrome brain. This is the first report of deregulated nucleolin-rRNA-mTOR-P70S6K signaling in the human Rett syndrome brain (178).
Genotype and phenotype. As genetic testing and knowledge is increasing, our understanding of genotype-phenotype correlations is expanding. This has practical implications for genetic counseling and tailoring individual therapies. One study looked at a sample including relatively large subsets of the most frequent mutations. Frequent missense mutations showed a specific profile in different areas of impairment. The R306C mutation, considered as producing mild impairment, was associated to a moderate phenotype in which behavioral characteristics were mainly affected. Mutations truncating the protein before and after the nuclear localization signal had an impact on the motor-functional and autonomy skills of the patients (65). Correlations of genotype and phenotype have also been made when looking at functional performance and rehabilitation needs (191), behavioral deficits (24), and severity and rate of speech and language regression (245).
In patients with epilepsy, various mutations in the MECP2 gene have a different influence on epilepsy, unrelated to the severity of the general Rett phenotype. Late truncating deletions had lower prevalence of epilepsy, whereas the p.R133C mutation, associated with a milder Rett syndrome phenotype, increased the risk for mild epilepsy. Those with the p.R255X mutation had an increased risk for epilepsy and severe epilepsy. The p.T158M and p.C306C mutations relatively increased the risk for severe epilepsy, but not for epilepsy occurrence (174). These findings might suggest a site-specific effect of MECP2 on epileptic pathways.
Early epidemiological studies have reported varying estimates of Rett syndrome before 1999, ranging from 0.22 to 22.03 per 10,000 females (271; 236). Since the introduction of genetic testing, the pattern and timing of Rett syndrome diagnosis have changed.
Studies show the incidence to be 0.5 to 1 per 10,000 live female births (20). It is very rare in males (162).
No means of prevention are known. Prenatal testing is available. In the future, the relatively normal development during the first 6 to 18 months of life may allow for pre-symptomatic therapeutic intervention, especially if newborn screening programs can identify affected females.
Clinical. Neul and colleagues provided revised diagnostic criteria for Rett syndrome and emphasized that it remains a clinical diagnosis because not all Rett syndrome patients have MECP2 mutations and not all patients with MECP2 mutations have Rett syndrome (170).
Percy and colleagues validated the revised diagnostic criteria in an analysis of 819 patients enrolled in a natural history study of Rett syndrome. Of the 819 patients, 765 females fulfilled 2002 criteria for classic (85.4%) or variant (14.6%) Rett syndrome (104). All those classified as having classic Rett syndrome fulfilled the revised main criteria, and all those with variant Rett syndrome met 3 of 6 main criteria in the 2002 classification, 2 or 4 main criteria in the revised system, and 5 of 11 supportive criteria in both (188). Early vocalization atypicality has been described in infants with Rett and has been hypothesized to be a potential model utilized to identify affected patients early (194).
Genetic. In addition to clinical features, genetic testing can establish or confirm the diagnosis. More available genetic testing has also broadened our knowledge of the disorder, allowed for earlier diagnosis, and expanded the clinical phenotype. Genetic testing is recommended in cases that are diagnosed clinically. In cases where the diagnosis is suspected as a possibility, although the patient does not have all the classic features, genetic testing should also be strongly considered.
In classical or atypical clinical variants of Rett syndrome, a PCR‐mutation screening of exons 3 and 4 of MECP2 gene should be first performed. If negative, further screening for large deletions or small MECP2 mutations in exons 1 and 2 should be carried on.
In case of suspected early onset Rett syndrome, with epileptic seizures or spasms or microcephaly even in males, CDKL5 mutation screening and FOXG1 should follow. In case of negativity, targeted resequencing consisting of ad hoc gene panels or whole exome sequencing are then recommended, together with an array comparative genomic hybridization (CGH) analysis to exclude microdeletions/microduplications on the whole chromosomal set. The high banding karyotype may have priority in males with Rett‐like phenotype and possible XXY aneuploidy (181).
Prenatal testing is available for families with an affected daughter who has an identified MECP2 mutation. Because the disorder occurs spontaneously in most affected individuals, however, the risk of a family having a second child with the disorder is less than 1% (215). Carrier genetic testing is also available. In some families of individuals affected by Rett syndrome, there are other female family members who have a mutation of their MECP2 gene but do not show clinical symptoms. These females are known as “asymptomatic female carriers.” Genetic testing is also available for sisters of girls with Rett syndrome who have an identified MECP2 mutation to determine if they are asymptomatic carriers of the disorder, which is an extremely rare possibility. In these cases, genetic counselling should be provided to families.
Please refer to www.genetests.org for information on specific testing and laboratories where testing can be done.
If no mutation is found or if patients do not fit clinical criteria, further diagnostic tests aimed at identifying other possible causes of their signs and symptoms should be performed. A standard workup for children with delay and seizures with no clear etiology should be done. Such tests may include the following:
Other. A metabolic workup can be done, including serum lactate, ammonia, pyruvate, and amino acids and urine organic acids. Depending on the specific presentation, further metabolic workup may be necessary. A referral to a metabolic specialist should be considered.
Chromosomal studies, including chromosomal microarray, karyotype, and testing for Angelman syndrome (chromosome 15) can be performed. A referral to a geneticist may be warranted. Epilepsy gene panels may be considered in some children with refractory epilepsy and delay with no clear etiology.
MRI brain and MRS of the brain should be performed if no specific diagnosis can be made to rule out brain structural abnormalities. It can also provide further information on genetic and metabolic conditions. Of interest, one group looked at quantitative surface and voxel-based morphological measurements in young children with Rett syndrome with MECP2 mutations (219). They demonstrated decreased total volumes of the cerebellum in Rett syndrome compared to gender- and age-matched controls. In contrast, global cerebral cortical surface areas, global/regional cortical thicknesses, the degree of global gyrification, and global/regional gray and white matter volumes were not statistically significantly different between the 2 groups. This suggests that early brain abnormalities associated with Rett syndrome with MECP2 mutations can be detected as regionally decreased cerebellar volumes (219).
In Rett syndrome, MRI of the brain does not provide any significant additional help in the diagnosis but can rule out other conditions (132). The MRI can show nonspecific findings, including cortical atrophy, particularly of the frontal and temporal lobes and the cerebellum. Corpus callosum hypoplasia and brainstem thinning have also been described (95). MRI volumetric analysis confirms decreased brain volume in Rett syndrome with global reductions in both grey and white matter. A selective vulnerability of the frontal lobes is also evidenced by the preferential reduction of blood flow, increased choline, and reduced n-acetyl aspartate (NAA) by MRS. There is also increased glucose uptake in these same regions as shown by ((18)F)-fluorodeoxyglucose (FDG) PET scans (166).
In patients with Rett syndrome, other ancillary tests can be performed. EEGs are a useful tool. They can help confirm the diagnosis in certain situations, help determine risk for seizures, and characterize epileptic from nonepileptic events.
In early stages, the EEG is often normal. Over time, the EEG shows a variety of abnormalities. Initially, there can be slowing of background activity or multifocal epileptiform abnormalities, especially in the midline central regions. Paroxysmal high-amplitude theta activity occurs over extended periods, related to spontaneous hyperventilation, and generalized slow spike wave activity can be seen. After 10 years, there is a general reduction in the epileptiform activity, but further slowing of the background rhythms and suppression can occur (248).
Visual evoked potentials are not routinely used in patients with Rett syndrome. One study showed that Rett syndrome patients displayed a slower recovery from the principal peak of the visual evoked potential response that was impacted by MECP2 mutation type. They also had lower visual spatial acuity (143). Visual evoked potentials may have a role in probing the neurobiological mechanism underlying functional impairment and in monitoring progression of the disorder and response to treatment.
Unfortunately, there is no cure for Rett syndrome. However, the goal should be to optimize health aspects so the child may demonstrate the capacity to learn new skills. Management should help to maintain or improve ambulation and range of motion, especially functional movements. It should aim at preventing deformities and preserve or improve use of hands. It should optimize communication and ability to make choices.
Further research is being done to understand the role of MECP2 in the pathophysiology of Rett syndrome. This would enable treatments to target the effects of mutated MECP2 protein on neurons and possibly help arrest the progressive nature of the syndrome. Neurobiologically-based drug trials are the ultimate goal in Rett syndrome (128).
The management of Rett syndrome consists of primarily symptomatic and supportive care. A multidisciplinary team approach is recommended due to the diverse multisystem clinical manifestations.
As soon as possible after diagnosis, supports should be offered to families, including psychosocial supports, genetic counselling, and links or contacts to community resources. Parent support groups can also be very beneficial to families.
Appropriate referrals to developmental pediatricians and working with schools for an appropriate education plan are crucial. A multimodal, individualized physical therapy program should be regularly recommended to patients with Rett syndrome in order to preserve autonomy and to improve quality of life (71).
Referral to early intervention should be made at the time of diagnosis. Early speech therapy, occupational therapy, and physical therapy are important.
Seizures. Seizures are common in children with Rett syndrome, especially in early childhood. Up to 85% of children will report seizure occurrence during their lifetime (88). However, it can sometimes be challenging to differentiate seizures from other nonepileptic movements or behaviors that are common in Rett syndrome. Breathing abnormalities, such as breath-holding and paroxysmal hyperventilation can mimic seizures. Motor activities, such as twitching, jerking, or tremors can also be confused with seizures. In addition, children with Rett syndrome can have cardiac arrhythmias, such as a prolonged QT interval, which can lead to paroxysmal episodes (216). Sleep disorders or autonomic dysfunction can also be on the differential diagnosis of seizures.
Prolonged video EEG monitoring is very helpful to characterize events. Some children may also benefit from sleep studies as sleep disorders are also common in Rett syndrome. Parental education on seizures can also assist in properly identifying and treating seizures. There are also incidences where seizures can be subtle and missed by parents (88).
Standard antiseizure medications can be used to treat the seizures. Choice of medications depends on seizure type, side effect profile, other drugs, etc. Sometimes children with Rett syndrome can be more sensitive to medications and may require slower dose titrations and weaning schedules. An Italian retrospective study looked at seizure medications in Rett syndrome and found that lamotrigine, sodium valproate, and carbamazepine can be used as drugs of first choice (193). One study observed different effectiveness of antiseizure medications based on age, and it suggested that clinicians consider age-dependency when prescribing appropriate antiseizure medications in the Rett population. Valproic acid was reported as the most effective antiseizure medication in younger girls (in 40% of the patients younger than 5 years of age and in 19% of the girls aged 5 to 9 years), and carbamazepine was reported as the most effective in the patients 15 years of age or older (251). However, valproic acid has been linked to a 3-fold increase of fracture risk in those with Rett patients (145). Moreover, it has been postulated that valproate by virtue of deacetylase inhibition might exacerbate the effects of MECP2 mutations (189).
A few studies on lamotrigine therapy in Rett syndrome demonstrate seizure reduction, decreased severity of stereotypic hand movements, and autistic behavior (135; 160). Topiramate, a drug with GABAergic and glutaminergic effects, has shown to lead to improvements in gait, respiratory function, and cognition (97). Levetiracetam is an effective antiseizure medication for Rett syndrome patients with treatment-resistant seizures (225). Other treatments for refractory seizures include the ketogenic diet, vagal nerve stimulator, and the newly reported total corpus callosotomy (244).
Sleep disorder. Polysomnography is recommended if there is suspicion of sleep disorder. Due to autonomic dysfunction, many children can have immature sleep patterns similar to those seen in infancy. Sleep-wake cycles are disrupted and immature. Proper sleep hygiene is important. Many children benefit from melatonin to help with sleep initiation. However, various other sleep medications can be used if required (266). Prolonged QT interval should be evaluated before selecting a safe pharmacologic agent for sleep (22).
Autonomic dysfunction. Various autonomic symptoms have been described in children with Rett syndrome. Poor pain discrimination can lead to injuries. Proper safety measures, including good foot wear and limb restraints to prevent self-injurious behavior, can prevent injuries. Reflex sympathetic dystrophy can occur and may need to be treated with neuropathic pain medications. Vasomotor changes in extremities usually to not require specific treatment. Autonomic responses can be used as a correlation for pain in nonverbal individuals (177).
Respiratory. Due to autonomic dysfunction, the respiratory system can also be affected. It is recommended that patients undergo monitoring in a respiratory physiology lab periodically. This can screen for apnea, abnormal breathing, tidal carbon dioxide levels, hemoglobin saturation, and pulse wave forms while the patient is awake and asleep. Medications that depress the respiratory system should be used with caution (258).
Children can present with several respiratory issues in their lifetime, including hyperventilation, breath holding, shallow breathing, and central or obstructive apnea.
Often children do not require any treatment for respiratory issues. Naltrexone has been used for central apnea in some children (186). If a child has alkalotic tetany secondary to hyperventilation, it is recommended the child breathes into a bag. Spinal fusion has been shown to be associated with reduced mortality and better respiratory health (54).
The first clinical trial of desipramine did not show clinical efficacy in improving the Apnea-Hypopnea Index (AHI), but a significant correlation between desipramine serum concentrations and improvement in AHI have provided relevant reasons to text the noradrenergic pathway in Rett syndrome (154).
Movements. Repetitive purposeless hand movements are common in Rett syndrome. Physical therapy and occupational therapy can be of assistance with recommending arms restraints, such as elbow splints. This can sometimes be helpful in training for specific hand skills, such as feeding or communication. It may also help with self-injurious behavior (25).
Medications are not typically used to stop the movements as often they can be sedating or have other side effects.
Language. Most with Rett syndrome will have language impairment, expressive more than receptive. Factors interfering with communication include cognitive impairment, delayed latency of response, delayed auditory processing, oral-motor dyspraxia, and dysarthria. Clinically, there can be a spectrum of language skills. Some with Rett syndrome will have no verbal language expression whereas others may have single words or phrases.
Speech therapy is very important in patients with preserved speech. Speech and occupational therapists can also work with the patient to help them coordinate their lips and tongue through various exercises using straws, bottles, cups, etc. Speech therapy can also help families with nonverbal communication. Some may be able to communicate with eye pointing, staring, or signs. The speech and occupational therapist can work with the family to coordinate a type of communication with the patient.
Communication boards, technological devices, and switch activated systems can help the child express needs and make choices for day-to-day things (25).
Assessments of cognitive functioning are usually extremely difficult because patients with Rett syndrome are largely nonverbal and have little or no purposeful hand use. These profound impairments make standard neuropsychological testing impossible, leaving the cognitive phenotype of Rett syndrome largely a mystery. Recent work using eye tracking, which minimizes the impact of these motoric and language problems, shows that communicative eye gaze is relatively preserved in Rett syndrome. The use of eye-tracking technology has been used to demonstrate communicational signals in a small group of girls with Rett syndrome (04). Another study examined eye tracking to understanding attention, a core cognitive ability, in Rett syndrome (206). They used gaze-based measures and eye-tracking technology, and they demonstrated that children with Rett syndrome have difficulty shifting attention and, to a lesser extent, disengaging attention, whereas with other disorders, problems with disengagement are paramount.
Feeding. Problems with feeding are very common. Even though patients may have a good appetite, weight gain can often be difficult. This is multifactorial. First, girls can have swallowing difficulties and immature chewing patterns. Early swallowing assessments are crucial to prevent complications and optimize nutrition. Some children require altered feeds, such as thickened feeds or positioning.
Second, there can be energy imbalances with calories used to sustain increased motor activities versus growth. Most are unable to feed themselves and do not develop mature feeding patterns. A referral to a dietician can be very helpful to ensure the child is getting adequate calories and nutrients.
A gastrostomy tube is sometimes needed to supplement nutrition in severe cases. In one study, it was found that frequent small feeds during the day with added carbohydrate foods not only maintained growth and weight gain, but had a definite influence on agitation and irritability in younger girls (26).
If there is evidence of gastro-esophageal reflux, standard reflux medications can be used.
Growth, including head circumference, weight, and body mass index should be plotted on a growth curve with follow up visits.
Drooling. Drooling can be a significant issue in children with Rett syndrome. Treatments include oral-motor treatment. Sometimes, medications are required, such as glycopyrrolate or oral Botox injections every few months.
Ophthalmology. A referral to pediatric ophthalmology should be made annually. Patients with Rett syndrome have developmental delay and tend to stare, which can make assessing vision challenging.
Dental. A pediatric dentist should assess children with Rett syndrome. They have a high incidence of bruxism. This may lead to tooth decay, tooth deterioration, enamel wear, temporomandibular joint pain, etc. Some children with severe bruxism have benefited from modified dental splints or other techniques, such as acupuncture (73).
Cardiac. Prolonged QT syndrome is commonly seen in Rett syndrome (216; 62). Twelve-lead ECGs or Holter monitors may be necessary for diagnosis. Medications that can exacerbate or prolong the QT interval or exacerbate arrhythmias should be avoided. One animal study found that Na(+) channel blockers should be considered for the clinical management of long QT in individuals with Rett syndrome (116).
Thyroid. Abnormalities of thyroid function are not rare in Rett syndrome. The possible relationship between these disorders and the Rett syndrome phenotype will need to be further studied. Children with Rett syndrome should be screened for potential thyroid dysfunction (227).
Musculoskeletal issues. Scoliosis is found in a high percentage of girls with Rett syndrome. This will carefully need to be followed as the child grows. Some are treating with bracing, and others may require surgery.
Many girls will develop increased tone over time. They may present with tightened heel cords or toe walking. Early physical therapy referral is important to prevent contractures or foot deformities. Stretching exercises, bilateral foot orthoses, Botox, and heel cord lengthening procedures may be required. Surgical fusion of early onset severe scoliosis has been found to increase survival in Rett syndrome (55).
Almost half of a population of Rett patients in a Japanese tertiary care center had either skin injuries or joint contractures (117). This emphasizes the importance of early interventions to attempt to prevent the occurrence of these.
Girls with Rett syndrome are at a higher risk of developing bone fragility and fractures at a young age. In Rett syndrome, a specific dysfunction of osteoblasts can also contribute to bone fragility. All Rett syndrome patients should be screened for impaired bone mineralization, and preventative measures, such as intravenous bisphosphonates, can be used to diminish the risk of fracture and restore bone density (138). One group demonstrated that annual injection of zoledronic acid improves bone status in children with Rett syndrome and cerebral palsy (260).
Agitation. It is important to find an underlying cause for the agitation. These can include various underlying issues, such as infections, seizures, pain, gall stones, fractures, or change in environmental factors. Once the underlying cause is found, this should be treated. If all other causes are excluded, children with agitation can be managed with conservative measures, such as frequent snacks, massage, warm baths, etc.
Occasionally pharmacological treatments are required, such as mood stabilizers, anti-opioids (naltrexone), or antipsychotic medications (quetiapine, risperidone). There are several reports in the literature about deep brain stimulation for treatment of mood disorders and memory in Rett syndrome (208). Glatiramer acetate was proposed as an intervention to improve behavior by increasing BDNF levels. However, when a clinical trial was run, 3 patients experienced reactions described as life-threatening, including apneas, seizures, and edema, necessitating epinephrine administration (173).
Psychosocial. The diagnosis of Rett syndrome can have a major impact on family function. It is important the family can be educated about the syndrome, complications, and disease progression. They should receive community resource and respite options. It can be beneficial for families to seek help with resources from a regional center, social worker, or a psychologist. A study examining maternal well-being of a child with Rett syndrome demonstrated that the best indicators of maternal wellbeing and overall family functioning were caregiver strain and the behavior of the child (142).
Medical home and transition to adult care. In early adolescence, discussion should be initiated about transition to adult health care. Discussion should include information about services, providers, and finances needed in adult years. It is also important to address long-term care of the child, including education and resources and options.
Alternative treatments. As there is no cure for Rett syndrome, many families search for treatments that will improve the child's symptoms and quality of life. Alternative or complementary therapies that have been tried in children with Rett syndrome include acupuncture, chiropractic treatment, myofascial release, massage therapy to loosen stiff muscles and joints, yoga, animal-assisted therapy (such as using therapy dogs), auditory integration training (which uses certain sound frequencies to treat speech and language problems), music therapy, and hydrotherapy (which involves swimming or moving in water) (151). At the present time, there is not much evidence for these therapies; however, some families report good results. It is encouraged that families discuss any alternative therapy with the medical team to ensure safety and how they can be integrated with the medical treatment.
Pharmacological treatments. Following are common medications used in Rett syndrome:
• Selective serotonin reuptake inhibitors: improve serotoninergic transmission, improve sympathovagal imbalance
Clinical trials. Since 1966 and the first clinical description of Rett syndrome, over 50 clinical trials testing therapeutic agents targeting motor, cognitive, and autonomous dysfunctions have been initiated. Furthermore, there have been few results from these trials that are clinically significant or that have clinical recommendations. Clinical trials can be challenging in Rett syndrome due to variable phenotypic severity. Quality of life is usually the primary outcome measure of clinical trials in Rett Syndrome, which is derived from clinical severity scores, communication assessments, EEG, plethysmographic recordings for breathing pattern analysis, and actigraphy for studying stereotypic hand movements.
Gene/epigenetic modifiers. Folate and betaine act on the DNA methylation pathway and increase the degree of methylation of the CpG binding proteins, leading to restoration of the Rett syndrome phenotypes in pre-clinical trials. However, a double-blinded, placebo-controlled, one-year study of folate-betaine therapy revealed no improvement in the Rett syndrome patients (86).
MeCP2 protein deficiency in Rett syndrome causes epigenetic changes in the creatine transporter gene, which leads to abnormal creatine metabolism (108). Creatine monohydrate dietary supplementation in Rett syndrome patients resulted in increased global DNA methylation but no significant improvement in motor and behavior assessments (72).
Growth factor therapy. Insulin-like growth factor-1 is able to penetrate the blood-brain barrier and stimulate proliferation of neural progenitors, neuronal survival, neurite outgrowth, and synapse formation (49). Preclinical trials used the tri-peptide fragment of IGF-1, which was shown to improve motor function, dendritic spine density and motility, and breathing rhythm in MECP2 mutant mice (241; 137). A clinical study examined the disease severity, social and cognitive ability, and changes in brain activity with EEG in Rett syndrome patients and controls. Significant improvement was noted in patients treated with insulin-like growth factor-1, including a greater endurance for social and cognitive testing (192).
A phase I study with mecasermin (rhIGF-1) in 12 patients with Rett syndrome demonstrated that rhIGF-1 is well tolerated and safe with positive outcomes in apnea, anxiety, and mood swings in Rett syndrome (130). The phase II study of 30 Rett syndrome patients in the post-regression stage demonstrated significant improvements in stereotypic behavior and social communication (176).
Trofinetide (glycyl-L-2-methylprolyl-L-glutamic acid) is an analog of the amino-terminal tripeptide of insulin-like growth factor 1 (IGF1). Rett mouse models demonstrate that IGF1 treatment improves disease symptoms (20; 141; 241). A study of trofinetide in 56 adolescent and adult patients with Rett syndrome was performed and demonstrated tolerability and clinical effectiveness (85). A subsequent double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome patients demonstrated that trofinetide at 200 mg/kg twice a day showed statistically significant and clinically relevant improvements relative to placebo on the Rett Syndrome Behavior Questionnaire, Rett Syndrome-Clinician Domain Specific Concerns-Visual Analog Scale, and Clinical Global Impression Scale-Improvement (84). The impacts of these 2 trials have laid a strong platform for the phase III trial (185).
BDNF boosters. BDNF is a molecule that has shown to have a role in neuronal survival and synaptic plasticity. MECP2 regulates the expression of BDNF gene (140). Low levels of BDNF have been found in those with Rett syndrome (48). Preclinical trials have been done to activate or mimic BDNF. Studies have demonstrated that BDNF overexpression in MECP2 mutant mice reversed behavioral phenotypes in animals and dendritic atrophy in primary neuron culture (33; 140). Transcranial Focused Ultrasound shows potential by increasing BNDF expression and resulting in modulation of human cortical function (242). A study in an animal model of Rett syndrome has additionally shown that treatment with D-cycloserine, an analog or the amino acid D-alanine with antibiotic and glycinergic activity, helps to partially restore lower BDNF levels in the brainstem and striatum, which may mitigate the severity of some of the neurobehavioral symptoms experienced by patients with Rett syndrome (164).
Glatiramer acetate (copaxone) was screened in phase I and II trials. The phase I trial was discontinued because of immediate postinjection response and severe adverse effects in 14 patients (173). In a phase II open label trial, there were improvements in gait velocity, memory, and breathholding. However, daily injections of copaxone caused life-threatening effects in the patients. A phase I clinical study to assess the safety and efficacy of oral fingolimod (FTY720) in children with Rett syndrome is being conducted, and no safety concerns have been reported yet (NCT02061137) (165).
NMDA receptor antagonist. Glutamate levels are increased in Rett syndrome (182). It is possible that very high levels of glutamate could hinder dendritic shape and synaptic number. Although preclinical trials have not tested the result of reducing glutamate transmission on the overall phenotype presentation in MECP2 mutant mice, it has been shown that the use of memantine, an NMDA receptor blocker, restored 2 short-term plasticity components, post-tetanic potentiation, and paired pulse facilitation (259). Ketamine, a NMDA receptor antagonist, ameliorated Rett syndrome symptoms and extended the life span of treated MECP2-null mice, and significant improvement was observed in cortical processing and connectivity (184). A phase I study of ketamine on Rett syndrome patients was terminated because of funding withdrawal (NCT02562820). Nevertheless, the phase II study to determine the safety and efficacy of the drug in Rett syndrome patients is ongoing (NCT03633058).
The metabotropic glutamate receptor 5 (mGlu5) protein, a key regulator of synaptic protein synthesis, is significantly reduced in the brains of individuals with Rett syndrome. Administration of a novel mGlu5 positive allosteric modulator, termed VU0462807, rescued synaptic plasticity defects and improved symptoms in a preclinical trial (90).
Dextromethorphan is a noncompetitive antagonist of the NMDA receptor. Dextromethorphan treatment in Rett syndrome patients improved clinical seizures, receptive language, and behavioral hyperactivity (NCT00593957). However, the primary endpoint of reduced spike activity was not met, and the study was terminated. However, a placebo-controlled trial has commenced (NCT01520363) (223).
Serotonergic drugs. Fluoxetine (a selective serotonin reuptake inhibitor) and buspirone (a serotoninergic type 1A agonist) exhibited positive impacts on respiratory dysfunction in Rett syndrome (91). An open-labeled clinical study (EudraCT Number: 2008–000,787-16) involving fluoxetine in France for Rett syndrome patients aged 8 to 28 years is ongoing. Venlafaxine and citalopram were tested in 15 Rett syndrome patients and showed no significant improvement in mood and behavior disorders (156).
Mitochondrial effectors. EPI-743 (α-tocotrienol quinone) belongs to the class of benzoquinones and has the potential to rescue the redox imbalance by increasing the intracellular glutathione level. A phase 2A randomized, placebo-controlled, 6-month trial failed to meet the primary endpoint of Rett syndrome severity score, but there was an increase in head circumference, oxygenation, and hand function (NCT01822249).
Omega-3 polyunsaturated fatty acids have been shown to partially rescue fatty acid abnormalities that are detectable in the Rett syndrome erythrocyte membranes (222). Therefore, this may be another potential treatment for Rett syndrome. Triheptanoin or UX007 is colorless oil that helps to improve the metabolism and energy production in mitochondrial disorders. Triheptanoin supplementation in MECP2-mutant mice led to improved mitochondrial morphology and improved energy production. This translated to improved motor coordination and increased lifespan in these mice (247).Two clinical trials have been registered and can be accessed at the following website:clinicaltrials.gov. The first is an open-label trial in Israel (NCT03059160); the other one is an open-labeled 10-subject clinical trial, which is ongoing in the United States (NCT02696044).
Metabolic boosters. L-Carnitine (3-hydroxy-4-N-trimethylamrnonium butyric acid) is an optically-active quaternary ammonium compound that is essential for mitochondrial energy production. A randomized controlled trial of L-carnitine in Rett syndrome demonstrated improvements in overall well-being and hand apraxia scale, but physical ability was not enhanced (62). The medium-term effects of L-carnitine were discerned to be improved sleep efficacy, energy production, and communication in 21 Rett syndrome patients (61). Long-term treatment with the drug reduced the risk of sudden death (98).
Lovastatin alters the cholesterol pathway, which leads to improve Rett syndrome symptoms related to gait, respiratory functions, and cognition. A phase II, dose-escalating trial (NCT02563860) of lovastatin in Rett syndrome patients showed positive impact on gait performance based on results posted at the following website:clinicaltrials.gov.
Gene/epigenetic modifier. Aminoglycosides can read through premature STOP codons in mutant genes and can be potentially useful as a pharmacological way to overcome premature transcriptional termination. This type of mutation occurs in 35% of North Americans with Rett syndrome (277; 207).
Tamoxifn is used to regulate gene expression using Cre-Lox recombination technique. In Mecp2 transgenic mice, tamoxifn was found to restore Mecp2 expression and reverse Rett syndrome phenotypes (201).
Dopaminergic drugs. Combined administration of levodopa and a dopa-decarboxylase inhibitor in Rett syndrome mouse models diminishes Rett syndrome-associated symptoms and increases life span. The improvement is particularly significant in those features controlled by the dopaminergic pathway in the nigrostriatum, such as mobility, tremor, and breathing (228).
Bromocriptine, a monoamine receptor agonist, was used in a small double-blind trial. Small improvements were noted in motor skills, but overall, no change in disease state was observed (272). This drug can also have possible negative side effects, such as liver dysfunction, vasospasm, and pulmonary stenosis, so further studies have not been done.
Serotonergic drugs. Pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R) has been shown to rescue specific behavioral and brain molecular alterations in MECP2-308 male mice, a Rett syndrome mouse model (43).
Potassium-chloride transporter (KCC2). Potassium-chloride transporter is a slow onset molecule with expression level reaching maximum later in development. The functional deficit of KCC2 may offer an explanation for the delayed onset of Rett syndrome symptoms. Studies suggest that restoring KCC2 function in Rett syndrome neurons may lead to a potential treatment for Rett syndrome (231).
Protein tyrosine phosphatase 1 B (PTP1B) inhibitors. PTP1B is upregulated in patients with Rett syndrome and in murine models. There is strong evidence that targeting PTP1B has potential as a viable therapeutic strategy for the treatment of Rett syndrome (234).
NMDA receptor modulators. Metabotropic glutamate receptor 7 (mGlu7) expression is reduced in cortical tissue of patients with Rett syndrome. The use of mGlu7-positive allosteric modulators restored deified in long-term potentiation, improved learning and memory, and corrected apneas in Rett mouse models (41).
Therapy with ifenprodil, a GluN2B antagonist, in MECP2 deficient mice and GluN2A-heterogenous mice caused reduced GluN2A expression and rescued synaptic composition of the NMDA receptors (161).
GABAergic drugs. GABAergic signaling dysfunction plays a critical role in Rett Syndrome symptomatology. NO-711, diazepam, and L-838,417 are GABA reuptake inhibitors. Treatment in Mecp2-defcient mice resulted in reduced apnea, restoration of the regular breath cycle, and improvement of locomotor ability (01).
Allopregnanolone is a neurosteroid of progesterone and a powerful allosteric modulator of the inhibitory GABA receptors. In MECP2 null mice, treatment with the drug elevated the amplitude of the GABAergic inhibitory postsynaptic currents, which confirms its potent therapeutic use in managing delayed onset Rett syndrome (124). Another GABAA receptor agonist, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride (THIP), improved motor function and social behavior when treated in Rett mice model (275). Treatment with tiagabine, a GABA reuptake inhibitor, showed prolongation of lifespan in Rett mice (59).
Mirtazapine is known to promote GABA release. It was effective in restoring somatosensory cortex thickness by fully rescuing pyramidal neurons dendritic arborization and spine density. It also normalized heart rate, breath rate, and anxiety levels and eliminated the hopping behavior observed in MECP2-null mice. Mirtazapine can represent a new potential pharmacological treatment (21).
Cholinergic drugs. Choline, a dietary micronutrient found in most foods, has been shown to be important for brain development and function. However, the exact effects and mechanisms are still unknown. One study found that 13 mg/day (1.7 times the required daily intake) of postnatal choline treatment to Mecp2-conditional knockout mice rescued not only deficits in motor coordination, but also their anxiety-like behavior and reduced social preference. Cortical neurons in the brains of Mecp2-conditional knockout mice supplemented with choline showed enhanced neuronal morphology and increased density of dendritic spines, suggesting a role of choline in modulating neuronal plasticity, possibly leading to behavioral changes, and hence, a potential for using choline to treat Rett syndrome (35).
Antiseizure medications. Phytocannabinoid cannabidivarin (CBDV) is a nonpsychoactive compound found to be an effective treatment for seizures. Fourteen days of CBDV treatment rescued behavioral impairments and brain alterations in MECP2 mice. This study reported that the increased G protein-coupled receptor levels in Rett syndrome can be upregulated by CBDV, which could be a novel therapeutic target in future (250).
Beta endorphins. Patients with Rett syndrome have been shown to have elevated levels of beta-endorphin in cerebral-spinal fluid (CSF) (27). Therefore, trials with naltrexone, an opiate antagonist, have been done. The results demonstrated that breathing patterns improved although motor behavior diminished overall (186).
Endocrine. Ghrelin is a hormone produced by enteroendocrine cells of the gastrointestinal tract. Ghrelin administration was studied in a small cohort of 4 Rett syndrome patients with severe dystonia and tremor. On multiple different scoring scales, 50% of patients had marked improvement of their dystonia and head tremors (268).
Inflammation/immunity. P2X7 receptors (P2X7Rs) are unique purinergic receptors with proinflammatory functions. An MECP2-deficient mouse model of Rett syndrome demonstrated that the border of the cerebral cortex exhibits increased number of inflammatory myeloid cells expressing cell-surface P2X7Rs. Total knockout of P2X7Rs in MECP2 deficient mice decreased the number of inflammatory myeloid cells, restored cortical dendritic spine dynamics, and improved the animals' neurologic function and social behavior (78).
Cytoskeleton-related genes and Rett syndrome. Studies have been carried out to investigate cytoskeleton-related genes in brain tissue of Rett syndrome patients. Decreased levels of TUBA1B and TUBA3 have been shown. These encode the ubiquitous alpha-tubulin and the neuronal specific alpha-tubulin in brain tissue in Rett and Angelman syndromes. Interestingly, the effects of MECP2 deficiency in these cells are completely reversed by introducing and expressing the human MECP2 gene (02). A report demonstrates that administration of cytotoxic necrotizing factor 1 (CNF1) to Rett syndrome mouse model markedly improves behavioral phenotype and astrocytic deficits (44). These results raise hopes for a cure of Rett syndrome and related MECP2 deficiency disorders.
Neuromodulation. Transcranial direct stimulation (tDCS) has been studied in 3 girls with Rett syndrome who had chronic language impairments (66). Coupled with behavioral training, tDCS-treated girls were seen to have improved language abilities, motor coordination, and neurophysiological parameters, suggesting that tDCS has a role in fostering brain plasticity.
Gene therapy. Rett syndrome was shown to be fully reversible in a mouse model of the disease, indicating that it could be amenable to gene therapy (102). This is of primary importance, as most Rett mutations occur de novo, and the disease is usually diagnosed when the symptoms are present, which also means that any therapeutic intervention will be administered to Rett patients after disease onset. To be efficient, any gene therapy vector has to reach the whole central nervous system, as it is globally affected in Rett syndrome. Gadalla and colleagues showed, as a proof of principle, a considerable improvement when neonatal Rett male mice were administered a gene therapy vector expressing the human MECP2e1 isoform by intracranial delivery (75). The phenotypic rescue was less pronounced when a more translational approach (that is, systemic administration of the therapeutic vector in juvenile Rett mice) was used. This first publication was followed by a second one reporting similar results in male Rett mice as well as a phenotypic improvement in female Rett mice (77).
One study, focusing on the route of administration, showed that the vector had better efficacy when administered via an intracerebrospinal fluid route (221). The neonatal intracranial administration of a truncated MECP2 was also shown to partially rescue the Rett phenotype (237), which shows that gene therapy can still be improved and benefit from new discoveries related to MECP2 biology. A study by Gadalla and colleagues indicates that gene therapy would also work in the case of certain missense mutations because the therapeutic vector was able to improve the Rett symptoms in a knock-in Rett mouse model (T158M) (76). Another therapeutic approach would be to directly correct the missense mutation by gene editing, as was done for a MECP2 duplication with the CRISPR-Cas9 system (263), or by RNA editing using the natural editing capability of the adenosine deaminases acting on RNA (ADAR) to correct G>A mutations (220). However, these techniques are still in their infancy, and so far their efficacy has been shown only in vitro.
Another possible therapy is based on the fact that a large majority of de novo MECP2 mutations have been identified in the paternal X chromosome (240). By identifying the locus of the mutation, an approach could be developed to turn off the mutant allele and activate the normal allele.
An adeno-associated virus gene therapy cassette has been studied in MeCP2-null mice (76). Direct cerebroventricular injection of this vector into MeCP2-null neonatal mice resulted in high brain transduction efficiency, increased survival and body weight, and amelioration of Rett-like phenotypes.
One study demonstrated decreased CHRM4 gene, which encodes M4 receptors, in an autopsy of a Rett patient (89). Potentiation of M4 was then demonstrated in mouse MeCP2 models to improve social and cognitive outcomes.
X chromosome reactivation. In female cells, 1 X chromosome is randomly inactivated, and this ensures the same expression of X-linked genes in both male and female cells. Therefore, in female patients with Rett syndrome, about half the cells express the mutant version of MECP2, whereas the other half expresses a normal MECP2 protein. Reactivation of the inactivated X chromosome (Xi), or at least of the (normal) inactivated MECP2 allele, could potentially cure Rett syndrome. In order to identify molecules involved in Xi reactivation, a short hairpin RNA (shRNA) library was used in 2 different studies (18; 226) and led to the discovery of factors modulating X-chromosome inactivation, including PDPK1 (3-phosphoinositide-dependent protein kinase 1) and AKA (Aurora kinase A), whose in vitro pharmacological inhibition was able to reactivate the Xi (18). In addition to those factors common to the 2 studies, Sripathy and colleagues reported that the BMP/TGFb pathway was strongly involved in X-chromosome inactivation both in vitro and in vivo (226). In another study, by combining a gene knockdown strategy using antisense oligonucleotides against Xist, one of the key XCI regulators, and a pharmacological approach, Carrette and colleagues demonstrated a synergistic effect on Xi reactivation in vitro and in vivo (30). These studies indicate that Xi reactivation is possible; however, the challenge now will be to translate these results into safe therapeutic interventions. The main issue will be to determine the impact of the induced global X-linked protein overdose following Xi reactivation.
No ultimate cure exists for this disease; instead, symptomatic treatments such as managing the respiratory ailments, improving the motor skills, and enhancing the intellectual ability are given (127).
As mentioned in the diagnostic workup section, prenatal testing is available for early detection of Rett syndrome. It is predominantly done if the family has a child with an MECP2 mutation identified.
Patients with Rett syndrome may have a higher incidence of respiratory or cardiac issues. A good history and exam is necessary prior to anesthesia. If there are concerns, anesthesia consultation may be required.
Anita Datta MD
Dr. Datta of the University of British Columbia has no relevant financial relationships to disclose.See Profile
Harvey B Sarnat MD FRCPC MS
Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.See Profile
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