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Rett syndrome(RTT)

MedGen UID:
48441
Concept ID:
C0035372
Disease or Syndrome
Synonyms: Autism, dementia, ataxia, and loss of purposeful hand use; Classic Rett Syndrome; Rett's disorder; RTT
SNOMED CT: Rett's disorder (68618008); Rett syndrome (68618008); Cerebroatrophic hyperammonemia (68618008); RTS - Rett syndrome (68618008); Rett disorder (68618008); Retts syndrome (68618008)
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Source: Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
 
Gene (location): MECP2 (Xq28)
 
Monarch Initiative: MONDO:0010726
OMIM®: 312750
Orphanet: ORPHA778

Disease characteristics

Excerpted from the GeneReview: MECP2 Disorders
The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years. [from GeneReviews]
Authors:
Simranpreet Kaur  |  John Christodoulou   view full author information

Additional descriptions

From OMIM
Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. It is characterized by arrested development between 6 and 18 months of age, regression of acquired skills, loss of speech, stereotypic movements (classically of the hands), microcephaly, seizures, and mental retardation. Rarely, classically affected males with somatic mosaicism or an extra X chromosome have been described (Moog et al., 2003).  http://www.omim.org/entry/312750
From MedlinePlus Genetics
PPM-X syndrome is a condition characterized by psychotic disorders (most commonly bipolar disorder), a pattern of movement abnormalities known as parkinsonism, and mild to severe intellectual disability with impaired language development. Other symptoms may include muscle stiffness (spasticity), exaggerated reflexes, and an abnormally small head (microcephaly). Affected males may have enlarged testes (macro-orchidism). Not all affected individuals have all these symptoms, but most have intellectual disability. Males with this condition are typically more severely affected than females, who usually have only mild intellectual disability or learning disabilities.  https://medlineplus.gov/genetics/condition/ppm-x-syndrome
From MedlinePlus Genetics
Rett syndrome is a brain disorder that occurs almost exclusively in girls. The most common form of the condition is known as classic Rett syndrome. After birth, girls with classic Rett syndrome have 6 to 18 months of apparently normal development before developing severe problems with language and communication, learning, coordination, and other brain functions. Early in childhood, affected girls lose purposeful use of their hands and begin making repeated hand wringing, washing, or clapping motions. They tend to grow more slowly than other children and about three-quarters have a small head size (microcephaly). Other signs and symptoms that can develop include breathing abnormalities, spitting or drooling, unusual eye movements such as intense staring or excessive blinking, cold hands and feet, irritability, sleep disturbances, seizures, and an abnormal side-to-side curvature of the spine (scoliosis).

Researchers have described several variant or atypical forms of Rett syndrome, which can be milder or more severe than the classic form.

Rett syndrome is part of a spectrum of disorders with the same genetic cause. Other disorders on the spectrum include PPM-X syndrome, MECP2 duplication syndrome, and MECP2-related severe neonatal encephalopathy. These other conditions can affect males.  https://medlineplus.gov/genetics/condition/rett-syndrome

Clinical features

From HPO
Short foot
MedGen UID:
376415
Concept ID:
C1848673
Finding
A measured foot length that is more than 2 SD below the mean for a newborn of 27 - 41 weeks gestation, or foot that is less than the 3rd centile for individuals from birth to 16 years of age (objective). Alternatively, a foot that appears disproportionately short (subjective).
Prolonged QTc interval
MedGen UID:
294666
Concept ID:
C1560305
Pathologic Function
A longer than normal interval (corrected for heart rate) between the Q and T waves in the heart's cycle. Prolonged QTc can cause premature action potentials during late phase depolarizations thereby leading to ventricular arrhythmias and ventricular fibrillations.
Abnormal T-wave
MedGen UID:
326862
Concept ID:
C1839341
Finding
An abnormality of the T wave on the electrocardiogram, which mainly represents the repolarization of the ventricles.
Cachexia
MedGen UID:
2773
Concept ID:
C0006625
Sign or Symptom
Severe weight loss, wasting of muscle, loss of appetite, and general debility related to a chronic disease.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Bruxism
MedGen UID:
676
Concept ID:
C0006325
Mental or Behavioral Dysfunction
Bruxism is characterized by the grinding of the teeth including the clenching of the jaw and typically occur during sleep, but also can occur while the affected individual is awake.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Truncal ataxia
MedGen UID:
96535
Concept ID:
C0427190
Sign or Symptom
Truncal ataxia is a sign of ataxia characterized by instability of the trunk. It usually occurs during sitting.
Stereotypical hand wringing
MedGen UID:
646835
Concept ID:
C0562479
Finding
Habitual clasping and wringing of the hands in the middle of the body, similar to a hand-washing movement.
Gait ataxia
MedGen UID:
155642
Concept ID:
C0751837
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to coordinate the movements required for normal walking. Gait ataxia is characteirzed by a wide-based staggering gait with a tendency to fall.
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Gait apraxia
MedGen UID:
266930
Concept ID:
C1510417
Disease or Syndrome
Gait apraxia affecting the ability to make walking movements with the legs.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Motor deterioration
MedGen UID:
356495
Concept ID:
C1866284
Finding
Loss of previously present motor (i.e., movement) abilities.
Intellectual disability, profound
MedGen UID:
892508
Concept ID:
C3161330
Mental or Behavioral Dysfunction
Profound mental retardation is defined as an intelligence quotient (IQ) below 20.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Intermittent hyperventilation
MedGen UID:
321811
Concept ID:
C1828017
Finding
Episodic hyperventilation.
Abnormality of the dentition
MedGen UID:
78084
Concept ID:
C0262444
Finding
Any abnormality of the teeth.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Rett syndrome in Orphanet.

Professional guidelines

PubMed

Leonard H, Downs J, Benke TA, Swanson L, Olson H, Demarest S
Lancet Neurol 2022 Jun;21(6):563-576. Epub 2022 Apr 25 doi: 10.1016/S1474-4422(22)00035-7. PMID: 35483386Free PMC Article
Banerjee A, Miller MT, Li K, Sur M, Kaufmann WE
Brain 2019 Feb 1;142(2):239-248. doi: 10.1093/brain/awy323. PMID: 30649225Free PMC Article
Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, Leonard H, Bailey ME, Schanen NC, Zappella M, Renieri A, Huppke P, Percy AK; RettSearch Consortium
Ann Neurol 2010 Dec;68(6):944-50. doi: 10.1002/ana.22124. PMID: 21154482Free PMC Article

Recent clinical studies

Etiology

Vilvarajan S, McDonald M, Douglas L, Newham J, Kirkland R, Tzannes G, Tay D, Christodoulou J, Thompson S, Ellaway C
Genes (Basel) 2023 Aug 11;14(8) doi: 10.3390/genes14081607. PMID: 37628658Free PMC Article
Gonzalez JN, Goldman S, Carter MT, Bain JM
Genes (Basel) 2023 May 26;14(6) doi: 10.3390/genes14061154. PMID: 37372334Free PMC Article
Sinnett SE, Boyle E, Lyons C, Gray SJ
Brain 2021 Nov 29;144(10):3005-3019. doi: 10.1093/brain/awab182. PMID: 33950254Free PMC Article
Pecorelli A, Cervellati C, Hayek J, Valacchi G
Int J Biochem Cell Biol 2016 Dec;81(Pt B):246-253. Epub 2016 Jul 15 doi: 10.1016/j.biocel.2016.07.015. PMID: 27425398
Mount RH, Charman T, Hastings RP, Reilly S, Cass H
J Child Psychol Psychiatry 2002 Nov;43(8):1099-110. doi: 10.1111/1469-7610.00236. PMID: 12455930

Diagnosis

Petriti U, Dudman DC, Scosyrev E, Lopez-Leon S
Syst Rev 2023 Jan 16;12(1):5. doi: 10.1186/s13643-023-02169-6. PMID: 36642718Free PMC Article
Pejhan S, Rastegar M
Biomolecules 2021 Jan 8;11(1) doi: 10.3390/biom11010075. PMID: 33429932Free PMC Article
Vidal S, Xiol C, Pascual-Alonso A, O'Callaghan M, Pineda M, Armstrong J
Int J Mol Sci 2019 Aug 12;20(16) doi: 10.3390/ijms20163925. PMID: 31409060Free PMC Article
Banerjee A, Miller MT, Li K, Sur M, Kaufmann WE
Brain 2019 Feb 1;142(2):239-248. doi: 10.1093/brain/awy323. PMID: 30649225Free PMC Article
Mount RH, Charman T, Hastings RP, Reilly S, Cass H
J Child Psychol Psychiatry 2002 Nov;43(8):1099-110. doi: 10.1111/1469-7610.00236. PMID: 12455930

Therapy

Petriti U, Dudman DC, Scosyrev E, Lopez-Leon S
Syst Rev 2023 Jan 16;12(1):5. doi: 10.1186/s13643-023-02169-6. PMID: 36642718Free PMC Article
Neul JL, Percy AK, Benke TA, Berry-Kravis EM, Glaze DG, Peters SU, Jones NE, Youakim JM
Contemp Clin Trials 2022 Mar;114:106704. Epub 2022 Feb 8 doi: 10.1016/j.cct.2022.106704. PMID: 35149233
Golub V, Reddy DS
Adv Exp Med Biol 2021;1264:93-110. doi: 10.1007/978-3-030-57369-0_7. PMID: 33332006
Sabus A, Feinstein J, Romani P, Goldson E, Blackmer A
Pharmacotherapy 2019 Jun;39(6):645-664. Epub 2019 Mar 27 doi: 10.1002/phar.2238. PMID: 30793794Free PMC Article
Kyle SM, Vashi N, Justice MJ
Open Biol 2018 Feb;8(2) doi: 10.1098/rsob.170216. PMID: 29445033Free PMC Article

Prognosis

Vilvarajan S, McDonald M, Douglas L, Newham J, Kirkland R, Tzannes G, Tay D, Christodoulou J, Thompson S, Ellaway C
Genes (Basel) 2023 Aug 11;14(8) doi: 10.3390/genes14081607. PMID: 37628658Free PMC Article
Rodríguez-Palmero A, Boerrigter MM, Gómez-Andrés D, Aldinger KA, Marcos-Alcalde Í, Popp B, Everman DB, Lovgren AK, Arpin S, Bahrambeigi V, Beunders G, Bisgaard AM, Bjerregaard VA, Bruel AL, Challman TD, Cogné B, Coubes C, de Man SA, Denommé-Pichon AS, Dye TJ, Elmslie F, Feuk L, García-Miñaúr S, Gertler T, Giorgio E, Gruchy N, Haack TB, Haldeman-Englert CR, Haukanes BI, Hoyer J, Hurst ACE, Isidor B, Soller MJ, Kushary S, Kvarnung M, Landau YE, Leppig KA, Lindstrand A, Kleinendorst L, MacKenzie A, Mandrile G, Mendelsohn BA, Moghadasi S, Morton JE, Moutton S, Müller AJ, O'Leary M, Pacio-Míguez M, Palomares-Bralo M, Parikh S, Pfundt R, Pode-Shakked B, Rauch A, Repnikova E, Revah-Politi A, Ross MJ, Ruivenkamp CAL, Sarrazin E, Savatt JM, Schlüter A, Schönewolf-Greulich B, Shad Z, Shaw-Smith C, Shieh JT, Shohat M, Spranger S, Thiese H, Mau-Them FT, van Bon B, van de Burgt I, van de Laar IMBH, van Drie E, van Haelst MM, van Ravenswaaij-Arts CM, Verdura E, Vitobello A, Waldmüller S, Whiting S, Zweier C, Prada CE, de Vries BBA, Dobyns WB, Reiter SF, Gómez-Puertas P, Pujol A, Tümer Z
Genet Med 2021 May;23(5):888-899. Epub 2021 Feb 17 doi: 10.1038/s41436-020-01075-9. PMID: 33597769
Pecorelli A, Cervellati C, Cordone V, Hayek J, Valacchi G
Free Radic Biol Med 2020 May 20;152:100-106. Epub 2020 Feb 28 doi: 10.1016/j.freeradbiomed.2020.02.023. PMID: 32119978
Pecorelli A, Cervellati C, Hayek J, Valacchi G
Int J Biochem Cell Biol 2016 Dec;81(Pt B):246-253. Epub 2016 Jul 15 doi: 10.1016/j.biocel.2016.07.015. PMID: 27425398
Naidu SB
Indian J Pediatr 1997 Sep-Oct;64(5):651-9. doi: 10.1007/BF02726119. PMID: 10771898

Clinical prediction guides

Vilvarajan S, McDonald M, Douglas L, Newham J, Kirkland R, Tzannes G, Tay D, Christodoulou J, Thompson S, Ellaway C
Genes (Basel) 2023 Aug 11;14(8) doi: 10.3390/genes14081607. PMID: 37628658Free PMC Article
Neul JL, Percy AK, Benke TA, Berry-Kravis EM, Glaze DG, Marsh ED, Lin T, Stankovic S, Bishop KM, Youakim JM
Nat Med 2023 Jun;29(6):1468-1475. Epub 2023 Jun 8 doi: 10.1038/s41591-023-02398-1. PMID: 37291210Free PMC Article
Neul JL, Percy AK, Benke TA, Berry-Kravis EM, Glaze DG, Peters SU, Jones NE, Youakim JM
Contemp Clin Trials 2022 Mar;114:106704. Epub 2022 Feb 8 doi: 10.1016/j.cct.2022.106704. PMID: 35149233
Sandweiss AJ, Brandt VL, Zoghbi HY
Lancet Neurol 2020 Aug;19(8):689-698. doi: 10.1016/S1474-4422(20)30217-9. PMID: 32702338
Naidu SB
Indian J Pediatr 1997 Sep-Oct;64(5):651-9. doi: 10.1007/BF02726119. PMID: 10771898

Recent systematic reviews

Petriti U, Dudman DC, Scosyrev E, Lopez-Leon S
Syst Rev 2023 Jan 16;12(1):5. doi: 10.1186/s13643-023-02169-6. PMID: 36642718Free PMC Article
Romero-Galisteo RP, González-Sánchez M, Costa L, Brandão R, Ramalhete C, Leão C, Jacobsohn L
Eur J Paediatr Neurol 2022 Jul;39:79-87. Epub 2022 Jun 12 doi: 10.1016/j.ejpn.2022.06.003. PMID: 35717810
Fetit R, Hillary RF, Price DJ, Lawrie SM
Neurosci Biobehav Rev 2021 Oct;129:35-62. Epub 2021 Jul 14 doi: 10.1016/j.neubiorev.2021.07.014. PMID: 34273379
Mahdi SS, Jafri HA, Allana R, Amenta F, Khawaja M, Qasim SSB
Int J Environ Res Public Health 2021 Jan 28;18(3) doi: 10.3390/ijerph18031162. PMID: 33525609Free PMC Article
Amoako AN, Hare DJ
J Appl Res Intellect Disabil 2020 Sep;33(5):808-827. Epub 2019 Dec 13 doi: 10.1111/jar.12694. PMID: 31833197

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