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Rett Syndrome

Retts Syndrome

Rett syndrome is an X-linked dominant neurodevelopmental disorder. It was first described in 1966 by Austrian pediatrician Andreas Rett.


The development of Rett syndrome happens in 4 stages [6]. The ages at which each stage occurs and the presentations for the stage are detailed below:

Stage I

This is known as developmental arrest and is seen in patients aged 6-18 month. Symptoms include:

  • Hypotonia
  • Delay in gross motor development
  • Lack of interest in playing
  • Inability to maintain eye contact
  • Wringing of the hands (the main sign of the disease)
  • Calm and dull appearance that is not seen in healthy infants of same age
  • Hyperventilation and holding of breath

Stage II

This is the rapid deterioration or regression stage and it is seen in children aged 1-4 years.

  • Behaviour consistent with autism is most dominant at this stage and so the child loses ability to speak and is unable to use the finger and hands naturally.
  • During wakefulness, hand-to-mouth movements, clapping, wringing etc. are noticeable. 

Stage III

This is the pseudostationary stage and is seen in children aged 2-10 years.

Stage IV

This is the Late motor deterioration stage and it is seen in children aged 10 years and above (>10 years).

Short Stature
  • A striking deceleration of growth has been found across all measurements in most girls with Rett syndrome who end up with short stature and microcephaly. The mortality (death) rate among children with Rett syndrome is increased (1.2% per year).[medicinenet.com]
  • She also had short stature, was underweight, and had microcephaly. Her EEG showed bilateral occipital dominant high-voltage slow spike and wave complexes. Her brain CT and MRI were normal.[dx.doi.org]
  • Despite aggressive perioperative resuscitation and ventilation support, the patient died 3 hours postoperatively secondary to refractory shock and hypoxemia.[ncbi.nlm.nih.gov]
  • In the pathogenesis and progression of classic RTT, red blood cell (RBC) morphology has been shown to be an important biosensor for redox imbalance and chronic hypoxemia.[ncbi.nlm.nih.gov]
Poor Feeding
  • He weighed 2810 g and subsequently spent 3 weeks in a special care nursery due to poor feeding, failure to thrive and apnoea.[doi.org]
Precocious Puberty
  • This is the first reported case of precocious puberty related to Rett syndrome.[ncbi.nlm.nih.gov]
  • Diagnostic evaluation revealed a mucosal tear in the posterior pharyngeal wall and an abscessed retropharyngeal lymph node, but she had no known history of trauma to account for these findings.[ncbi.nlm.nih.gov]
  • CONCLUSIONS: Dysphagia was primarily limited to oral preparatory phases, while the pharyngeal phase was normal in most patients. The high percentage of dysphagia suggests the need to accurately monitor the feeding capability of RS children.[ncbi.nlm.nih.gov]
  • Pia Bernardo, Enza Raiano, Gerarda Cappuccio, Raffaele Dubbioso, Carmela Bravaccio, Emilia Vergara, Silvio Peluso, Fiore Manganelli and Marcello Esposito, The Treatment of Hypersalivation in Rett Syndrome with Botulinum Toxin: Efficacy and Clinical Implications[doi.org]
  • He has a prominent rotary nystagmus, which has attenuated with age, and striking bilateral pupillary constriction (miosis). He has periodic breathing while awake and asleep.[doi.org]
Advanced Bone Age
  • Precocious puberty is characterized by premature breast and pubic hair development, and advanced bone age development at 8 years of age. We present a case of Rett syndrome and precocious puberty in a 6-year-old girl.[ncbi.nlm.nih.gov]
Severe Osteoporosis
  • The findings support the ability (in one case) to reverse the progression of osteoporosis in individuals with Rett syndrome showing severe osteoporosis with multiple fractures.[ncbi.nlm.nih.gov]
Round Face
  • He showed dysmorphic features including round face, anteverted nostrils, and tented upper lips. Brain magnetic resonance imaging showed hypoplasia of the frontal lobes and the rostral part of the corpus callosum.[ncbi.nlm.nih.gov]
  • Mutations in the P/Q type calcium channel CACNA1A have been implicated in epileptic encephalopathy, familial hemiplegic migraine, episodic ataxia 2, and spinocerebellar ataxia 6, but not Rett syndrome.[ncbi.nlm.nih.gov]
  • RTT clinical expression is typically characterized by loss of purposeful hand movements, severe mental retardation and motor impairment, breathing disorders, ataxia and increased risk of sudden death.[ncbi.nlm.nih.gov]
  • Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements.[ncbi.nlm.nih.gov]
  • The affected female is normal until the age of 6-25 months when progressive loss of voluntary control of hand movements and communication skills; ataxia; seizures; autistic behavior; intermittent hyperventilation; and hyperammonemia appear.[icd10data.com]
  • In males, this condition is described as MECP2 -related severe neonatal encephalopathy. autism-dementia-ataxia-loss of purposeful hand use syndrome Rett disorder Rett's disorder Rett's syndrome RTS RTT Chahrour M, Zoghbi HY.[web.archive.org]
Abnormal Gait
  • Rett syndrome is a neurodevelopmental genetic disorder, characterized by developmental delay, hand stereotypies, abnormal gait, and acquired microcephaly. Epilepsy is very common in Rett syndrome and can be medically intractable.[ncbi.nlm.nih.gov]
  • gait scoliosis decreased head circumference usually starts to become evident at 5-6 months poor circulation indicated by cold, blue extremities Imaging Radiographs recommended views AP pelvis findings coxa vara scoliosis films findings C-shaped curve[orthobullets.com]
  • Mecp2 -null male mice acquire neurological phenotypes reminiscent of RTT at 6 weeks after birth, including hypoactivity, abnormal gait, cognitive defects and breathing problems, leading to death at 6–12 weeks of age ( 14, 15 ).[doi.org]
Neurologic Manifestation
  • Neuroimaging may be used to exclude other causes of the neurological manifestations. ECG and possibly 24-hour ECG may be needed, as there is an association with cardiac arrhythmias.[patient.info]
Hand Tremor
  • We have noticed some evidence of a mild learning disability and fine hand tremor in the mother, although these abnormalities were only detected in retrospect after a familial mutation was identified.[doi.org]
Mental Deterioration
  • Eri Takeshita, Yoshiaki Saito, Eiji Nakagawa, Hirofumi Komaki, Kenji Sugai, Masayuki Sasaki, Atsuo Nezu, Junichi Kitamura, Masayuki Itoh, Yoshie Sawano and Yu-ichi Goto, Late-onset mental deterioration and fluctuating dystonia in a female patient with[doi.org]


Females that present any of the clinical presentations above are subjected to genetic testing to properly establish the presence of the condition [7] [8] [9]. In patients where MECP2 mutation is not found, it is important to undergo other diagnostic tests that are aimed at finding out the possible causes of the signs and symptoms being experienced.

T Wave Abnormality
  • This may be due, in part, to heart irregularities, specifically a prolonged QT interval and T-wave abnormalities.[rarediseases.org]
White Matter Lesions
  • Magnetic resonance imaging (MRI) revealed extensive white matter lesions, with anti-MOG antibodies detected in the serum and cerebrospinal fluid, resulting in an initial diagnosis of anti-MOG antibody encephalitis.[ncbi.nlm.nih.gov]


At present, there is no cure for the Rett syndrome. However, studies have demonstrated that restoration of the functions of the MECP2 may bring about a cure [10]. The treatment of the condition focuses on management. This includes the following:

  • Management of gastrointestinal issues like reflux and constipation and nutritional poor weight gain issues
  • Surveillance of scoliosis
  • Surveillance of long QT syndrome by annual ECG
  • Increasing the patient's communication skills, especially with augmentative communication strategies
  • Parental counselling
  • Modifying social medications
  • Provision of sleep aids


It is not easy to predict the developmental potential for patients with the Rett syndrome. Some individuals with this syndrome are able to maintain and achieve some functional skills [5]. Around 60% of RS patients are able to retain their abilities to ambulate. Others lose ambulation and due to scoliosis, dystonia, or atrophy, they may never walk.

The survival rate is poor in individuals that are 10 years or older and the 35-year survival rate is placed at 70%. Death may be sudden and is often followed by secondary pneumonia. Some of the risk factors commonly seen are difficulty with swallowing, loss of mobility and seizures. It is however, important to note that life expectancy is better in patients with Rett syndrome in comparison to patients with profound intellectual disability. The 35-year survival rate for the latter is only 27%.


Rett syndrome is caused genetically by mutations that occur in the MECP2 gene that is found on the X chromosome [2]. It can arise sporadically or from germline mutations. Rett syndrome was first described via clinical observations but the diagnosis becomes definitive only when the defect in the MECP2 gene becomes definitive. However, there have been some rare cases of the condition where the MECP2 remains unaffected.


Approximately, the incidence of Rett syndrome occurs is 1 case per 23,000 live female births. In some countries, wide variations have been reported with some of them posting figures showing 1 case per 10,000 live female births [3]. Figures in Japan suggest 1 case per 45,000 females aged 6 to 14. Variations in incidence may be due to the inclusion of atypical and/or variant forms of this condition. The atypical forms include congenital RS, preserved speech variants, as well as milder forms with later onset of regression.

The syndrome becomes evident clinically by 2 to 4 years of age, however the neurodevelopmental malfunction in children begin when they are 6 to 18 months or younger.

The patients identified are often female because the disease is X-linked. Most of the males that have the syndrome are believed to die in utero.

Studies have shown no racial variations of the syndrome as well.

Sex distribution
Age distribution


The severity and symptom of the RS condition is dependent on both the percentage of defective genes that are activated as well as the type of mutation responsible for the condition [4]. Varying mutation types have been seen in the 3 coding regions of the MECP2 gene and most of these cause truncations and missense proteins.

The mutations in the MECP2 gene bring about a loss of function of this protein with an unregulated expression of the genes that are normally affected. Some of these are crucial in the development of the nervous system past the early stages. The nervous system is the primary site of the condition but the specific target genes remain unknown. Due to the dysfunction of the MECP2 gene, astrocyte function is abnormal in Rett syndrome patients.


Rett syndrome cannot be prevented.


Formerly known as cerebroatrophic hyperammonemia, Rett syndrome (RS) is a genetic and neurologic disorder that affects the grey matter of the brain [1]. It is a very rare condition that is seen predominantly in females with occasional occurrence in males.

The common clinical features are deceleration in head growth and small hands and feet. Other common symptoms are repetitive hand movements such as continuously putting hand in mouth and hand wringing. Growth failure, scoliosis and constipation are also common and they prove the most problematic amongst all symptoms. Individuals with this condition are prone to gastrointestinal disorders and as much as 80% of affected people have seizures. They generally do not have any verbal skills and more than 50% of those affected do not walk.

Patient Information

Rett syndrome is a genetic disorder that has been classified as rare. It affects the way the brain develops and is seen almost entirely in girls.

Babies that have this condition develop normally at first but the symptoms become visible by the time they are 6 months old. As time passes, children with the condition show increasing difficulty with movement, communication and coordination. This often affects their ability to use their hands, walk and communicate.

Presently, there is no known cure for the condition but potential treatments are being considered. Treat for now is focused on improving movement and communication and also providing care and support for the affected children and their families.



  1. Kubota T, Miyake K, Hirasawa T. Role of epigenetics in Rett syndrome. Epigenomics. Oct 2013;5(5):583-92.
  2. Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat Genet. Oct 1999;23(2):185-8.
  3. Dayer AG, Bottani A, Bouchardy I, Fluss J, Antonarakis SE, Haenggeli CA, et al. MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother. Brain Dev. Jan 2007;29(1):47-50. 
  4. Hoffbuhr K, Devaney JM, LaFleur B. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. Jun 12 2001;56(11):1486-95.
  5. Huppke P, Laccone F, Kramer N, et al. Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet. May 22 2000;9(9):1369-75. 
  6. Rett A. [On a unusual brain atrophy syndrome in hyperammonemia in childhood]. Wien Med Wochenschr 1966; 116:723.
  7. Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol 2010; 68:944.
  8. Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999; 23:185.
  9. Allen RC, Zoghbi HY, Moseley AB, et al. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992; 51:1229.
  10. Cheadle JP, Gill H, Fleming N, et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet 2000; 9:1119.

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Last updated: 2019-07-11 22:10