Rett Syndrome


Article Author:
Gurneet Chahil


Article Editor:
Pradeep Bollu


Editors In Chief:
Chaddie Doerr


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
4/4/2019 3:50:39 PM

Introduction

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.[1][2][3]

Etiology

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. [4][5]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.[6]

Epidemiology

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.[7]

Pathophysiology

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.

Histopathology

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.

Evaluation

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.[8][9][10]

Treatment / Management

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.[11][12][13][14]

Differential Diagnosis

RTT can often be misdiagnosed. Important differential diagnoses to consider are cerebral palsy, autism, Angelman syndrome, and non-specific developmental delay.

Staging

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.

Prognosis

The life expectancy of an induvial with RTT can vary depending on the type of MECP2 mutation inherited [20]. Typically RTT individuals survive into middle age and recent studies suggest they may survive longer.

Enhancing Healthcare Team Outcomes

The diagnosis and management of RETT syndrome ie very difficult. The disorder is best managed by a multidisciplinary team.

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.

The outlook for patients with RETT syndrome is guarded. Most have a reduced life span and a poor quality of life.[15] (Level V)


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    Contributed by Gurneet Chahil
Attributed To: Contributed by Gurneet Chahil

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Rett Syndrome - Questions

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Rett syndrome is best described by which statement?



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What stage of the Rett syndrome is characterized by normal wave?



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The EEG in Rett syndrome shows changes corresponding with the stage of the disease. At what stage are there focal sharp or spike waves especially at the centroparietal area?



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Select the criteria necessary for diagnosis of Rett syndrome.



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A normally developing 2-year-old girl begins to show loss of developmental milestones, stops speaking, and almost always is wringing her hands. She is noted to have breath-holding episodes that alternate with hyperventilation. What is the most likely diagnosis?



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What stage of the Rett syndrome is characterized by generalized slow spike wave?



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What type of inheritance pattern is seen in Rett syndrome?



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Which of the following genes has been linked to the development of Rett syndrome?



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A 4 year old girl is noted by the occupational therapist to have behaviors or hand washing and wringing. The parents state there is a problem with hand skill progress. Which of the following diagnoses is most probable?



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Select the primary goal in treatment of Rett syndrome in children.



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Which of the following is false regarding Rett syndrome?



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Which of the following treatments apply to Rett Syndrome?



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A 15 month old female is brought to the office for evaluation for seizures. The patient has started to have a repetitive, stereotyped hand-wringing movement. There are no known triggers or patterns to this movement. The patient also has a history of developmental delay; however, on further history, the patient has actually regressed. She crawled at 11 months of age but is no longer crawling at all as of 3 months ago. Physical exam is notable for significant microcephaly. Which of the following are true?



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Mutations in which gene are thought to be found in the pathogenesis Rett syndrome (RTT)?



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What is seen on autopsy in the brain of a patient with Rett syndrome?



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Which of the following statements is false in regards to the mandatory criteria required for a diagnosis of typical Rett syndrome?



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Which of the following statements is incorrect?



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Which of the following criteria must be met to confirm a diagnosis of atypical Rett syndrome?



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Rett Syndrome - References

References

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Schönewolf-Greulich B,Bisgaard AM,Møller RS,Dunø M,Brøndum-Nielsen K,Kaur S,Van Bergen NJ,Lunke S,Eggers S,Jespersgaard C,Christodoulou J,Tümer Z, Clinician's guide to genes associated with Rett-like phenotypes-Investigation of a Danish cohort and review of the literature. Clinical genetics. 2019 Feb;     [PubMed]
Sadeghi S,Shevell M, Consideration of Genetic Diagnoses of Developmental Delay in Children of Consanguineous Families. Seminars in pediatric neurology. 2018 Jul;     [PubMed]
Jefferson A,Leonard H,Siafarikas A,Woodhead H,Fyfe S,Ward LM,Munns C,Motil K,Tarquinio D,Shapiro JR,Brismar T,Ben-Zeev B,Bisgaard AM,Coppola G,Ellaway C,Freilinger M,Geerts S,Humphreys P,Jones M,Lane J,Larsson G,Lotan M,Percy A,Pineda M,Skinner S,Syhler B,Thompson S,Weiss B,Witt Engerström I,Downs J, Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence. PloS one. 2016;     [PubMed]
Leonard H,Ravikumara M,Baikie G,Naseem N,Ellaway C,Percy A,Abraham S,Geerts S,Lane J,Jones M,Bathgate K,Downs J, Assessment and management of nutrition and growth in Rett syndrome. Journal of pediatric gastroenterology and nutrition. 2013 Oct;     [PubMed]
Vignoli A,La Briola F,Peron A,Turner K,Savini M,Cogliati F,Russo S,Canevini MP, Medical care of adolescents and women with Rett syndrome: an Italian study. American journal of medical genetics. Part A. 2012 Jan;     [PubMed]
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