Rett syndrome (RTT) is a neurodevelopmental disorder in which regression of previously acquired skills follows a period of typical development. RTT can present with a multitude of symptoms including but not limited to a deceleration in head growth, gait abnormalities, loss of purposeful hand movements often replaced with repetitive stereotypical movement (hand-wringing), loss of speech and breathing abnormalities. RTT is associated with a complex phenotype and has been classified into typical, atypical, and variant presentations. Approximately 90% of reported cases of RTT inherit mutations of the methyl-CpG-binding protein 2 (MECP2) gene. Some atypical cases of RTT may result from mutations in cyclin-dependent kinase-like 5 (CDKL5). Mutations in MECP2 have been associated with impacting the development of neurons and axodendritic connections. Jellinger and Seitelberger (1986) were the first neuropathologists to identify and describe the pathology behind RTT. They found that the brain in patients of RTT weighed less, and the neurons of the substantia nigra pars compacta contained less melanin in comparison to the age-matched controls. Although RTT was thought to be exclusive to females, males with the phenotype and MECP2 mutations are now being defined.
RTT is an X-linked dominant condition with lethal consequences in hemizygous males. Mutations in MECP2 are found in the majority of classic RTT cases; recent studies found 2 additional genes, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) involved in the pathogenesis of RTT. The spectrum of mutation types includes missense, nonsense, and frameshift mutations. Mutations affecting the NLS region of MECP2 or early truncating mutations are responsible for a more severe phenotype in comparison to missense mutations, whereas C-terminal deletions are associated with milder phenotypes. The R133C mutation is generally associated with a milder variant of RTT often with preserved speech. The MECP2 protein is responsible for 2 main functioning roles: the methyl-binding domain, which specifically binds to the methylated CpG dinucleotides, and the transcription repression domain, which recruits repressor proteins that inhibit gene transcription. Mutations in an X-linked gene CDKL5 have been reported in patients with a seizure variant of RTT. It is important to note that there is a wide spectrum of mutations associated with disease severity and close to 30 different types mutations can cause RTT.
RTT is one of the most frequent causes of mental disability in females, with an incidence of 1 in 10,000 to 15, 000. A population-based registry in Texas reported a prevalence of classic RTT as 1 per 22,800 females (0.44 per 10,000) from ages 2 to 18. RTT was originally thought to only occur in females and males with RTT were not considered to be viable. Further investigations on the incidence and prevalence of RTT in males are needed. A systematic review conducted in Texas in 2015 reported a total of 57 cases of RTT in males and a population study showed the incidence of RTT in males was not more predominant in any particular race.
Approximately 95% of RTT is the due to MECP2 mutations in the region of the gene methyl CpG-binding protein. Recent studies suggest MECP2 has both repressor and activator transcription activities. The exact mechanism of how MECP2 mutations lead to RTT is not yet known. A possible theory is that a deficiency of MECP2 causes an inability of synaptic maturation in the cortex. Another hypothesis is the lack of MECP2 disrupts the metabolism of brain cholesterol resulting in abnormal neuronal development. There have also been studies suggesting the failure of dendritic arborization in the cortex has led to abnormal neuronal signaling resulting in the lack of maturation of the autonomic nervous system, along with the motor and cortical regions. Recent evidence suggests that MECP2 is also expressed in glial cells and glial cell dysfunction caused by a change in DNA methylation could also be involved in the pathogenesis of RTT.
On autopsy, an RTT brain does not show signs of inflammation or degeneration. However, there is an overall decrease in the size of the brain and individual neurons. A 12% to 34% reduction in brain weight has been reported, most prominent in the prefrontal, posterior frontal and anterior frontal regions. These findings suggest that RTT is a neurodevelopmental and not a neurodegenerative process. The neuronal cell size is decreased, but there is an increase in neuronal cell packing in the hippocampus along with delayed neuronal maturation and synaptogenesis in the cerebral cortex.
MECP2 mutations alone are not enough to make a diagnosis of RTT. RTT is still considered a clinical diagnosis and is divided into typical and atypical presentations. The diagnostic criteria for a typical presentation require the presence of regression in addition to the criteria mentioned above main criteria plus the exclusion criteria must be met (see Table 1). In typical RTT, there will be a regression of purposeful hand use and spoken language resulting in a hand-wringing movement and abnormal gait. A stage of stabilization will often follow regression, and sometimes there will even be an improvement. Not all individuals with typical RTT will have postnatal deceleration in head growth. The diagnostic criteria for atypical RTT require the presence of regression plus 2 out of the 4 main criteria in addition to 5 out of the 11 supportive criteria (see Table 2). The above-mentioned criteria for typical RTT and atypical RTT apply to both males and females.
Currently, there is no cure for RTT, and medical management is aimed to provide symptomatic relief for patients through a multidisciplinary approach. Some of the medical concerns that need to be addressed in RTT patients include seizure disorders, behavioral alterations, sleep disorders, breathing irregularities, cardiac dysfunction (prolonged QT interval), gastrointestinal dysfunction and bone fractures. Approximately 60% of patients with RTT suffer from some seizure disorder. Treatment options to alleviate seizures include valproate, lamotrigine, levetiracetam carbamazepine, and AEDs. Behavioral alterations most often anxiety can be best addressed with serotonin reuptake inhibitors (SSRIs). RTT patients often have difficulty initiating sleep and frequent nighttime awakening, which can be managed with proper sleep hygiene and trazodone once airway obstructions and other causes are ruled out. Breathing irregularities can include, apnea, hyperventilation, and breath holding. Successful management of these irregularities can be difficult. However, precautions should be taken to avoid medications that alter breathing patterns, for example, opioid medications. Cardiac irregularities include a prolonged QT interval. This can be more difficult to manage in patients with RTT compared to the general population. Studies in mice with MECP2 mutations suggest that beta blockers may not be sufficient. Precautions should be taken to avoid medications that would further prolong the QT interval, for example, macrolides. Bone fractures are 4 times more common in RTT patients compared to the general population, and vitamin D levels should be closely monitored and supplemented as required. Digestive problems such as gastroesophageal reflux disease (GERD) and constipation are common in RTT patients and can be managed with calcium carbonate, histamine H2 receptor blockers (avoid cimetidine), and an increase in fiber intake. Other treatment options include physical therapy, speech therapy, occupational therapy, and psychosocial support for families. Management of these conditions can substantially improve the quality of life of RTT patients and should not be overlooked.
RTT can often be misdiagnosed. Important differential diagnoses to consider are cerebral palsy, autism, Angelman syndrome, and non-specific developmental delay.
Before the RTT criteria revisions and the discovery of MECP2, a staging system was implemented as a guide for clinicians to track the clinical course of RTT. It is important to note that the staging system does not predict life expectancy and should not be used for diagnostic purposes. Stage 1 begins around 6 to 18 months and involves developmental arrest. Some signs include limited eye contact, deceleration of head growth, non-specific hand-wringing and gross motor delays. Stage 2 onset is between the ages of 1 to 4 and consists of regression and rapid deterioration. Stage 2 is characterized by stereotypic hand movement (hand-wringing or washing), loss of speech, irritability and disturbed sleep. Stage 3 onset is between the ages of 2 to 10 is characterized by improvement in behavior, communication skills, and hand use. Stage 4 onset is after the age of 10 years and is characterized by dystonia, reduced mobility, and bradykinesia.
The life expectancy of an induvial with RTT can vary depending on the type of MECP2 mutation inherited . Typically RTT individuals survive into middle age and recent studies suggest they may survive longer.
The diagnosis and management of RETT syndrome ie very difficult. The disorder is best managed by an interprofessional team.
Currently, there is no cure for RTT, and medical management is aimed to provide symptomatic relief for patients through an interprofessional approach. Some of the medical concerns that need to be addressed in RTT patients include seizure disorders, behavioral alterations, sleep disorders, breathing irregularities, cardiac dysfunction (prolonged QT interval), gastrointestinal dysfunction and bone fractures. Approximately 60% of patients with RTT suffer from some seizure disorder.
The outlook for patients with RETT syndrome is guarded. Most have a reduced life span and a poor quality of life. (Level V)
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