Rett syndrome (ORPHA:778)
A rare severe, X-linked, neurodevelopmental disorder characterized by rapid developmental regression in infancy, partial or complete loss of purposeful hand movements, loss of speech, gait abnormalities, and stereotypic hand movements, commonly associated with deceleration of head growth, severe intellectual disability, seizures, and breathing abnormalities. The disorder has a progressive clinical course and may associate various comorbidities including gastrointestinal diseases, scoliosis, and behavioral disorders.
Epidemiology
The disorder affects approximately 1 in 10,000 live female births. The disease has been occasionally reported in males, usually with a lethal course before birth or in early infancy.
Clinical description
Classic or typical Rett syndrome (RTT) primarily affects girls and is characterized by apparently normal psychomotor development during the first 6-18 months of life followed by developmental stagnation with rapid regression in language and motor abilities, and subsequent long-term plateauing of skills. Repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures (60-80%), and acquired microcephaly. There is a wide variability in the rate of disease progression and severity. A number of males with a phenotype comparable to females with classical RTT have been described.
Etiology
Pathogenic variants in the X-linked gene methyl CpG-binding protein 2 (MECP2; Xq28) are found in more than 95% of classic RTT cases. The most common mutation involves a C to T transition at CpG dinucleotides; however, the spectrum of mutation types includes missense, nonsense, and frameshift mutations, with over 300 unique pathogenic nucleotide changes described, as well as deletions encompassing whole exons. Different phenotypes to classical RTT have been described in association within MECP2 pathogenic variants in males and females.
Diagnostic methods
The clinical diagnosis of RTT is based on consensus clinical criteria. These include one necessary criteria i.e. presence of regression plus four main criteria that are absolutely required for the diagnosis of typical RTT that include (i) partial or complete loss of acquired purposeful hand skills, (ii) partial or complete loss of acquired spoken language, (iii) gait abnormalities, (iv) stereotypic hand movements. Genetic testing identifies variants in MECP2 in 95-97% of individuals with typical RTT, but is not mandatory for RTT diagnosis.
Differential diagnosis
Differential diagnosis includes autism spectrum disorder; Angelman syndrome in which early development before 6 months is abnormal; CDKL5 deficient disorders in which early onset seizures are distinctive from RTT; FOXG1 syndrome in which congenital microcephaly and corpus callosum abnormalities are not usually found in RTT.
Antenatal diagnosis
Prenatal screening should be discussed in families with a proband having a pathogenic mutation.
Genetic counseling
As pathogenic MECP2 mutations in RTT patients are mostly de novo, the recurrence risk for future pregnancies is low, although germline mosaicism has been reported.
Management and treatment
Management is mainly symptomatic, focused on optimizing each patient's abilities through a multidisciplinary approach. Attention should be paid to scoliosis and the development of spasticity, as well as to effective communication strategies. Psychosocial support for families is essential. Pharmacological approaches aim at improving sleep disturbances, breathing disturbances, seizures, stereotypic movements and general well-being. As RTT patients have an increased risk of life-threatening arrhythmias associated with a prolonged QT interval, avoidance of a number of drugs is recommended (e.g. macrolide antibiotics).
Prognosis
The clinical picture evolves in stages over a number of years. Patients have been reported to live into middle age and beyond.

                            Last update: 
                            January 2021


                            - Expert reviewer(s): 
                            Pr Nadia BAHI-BUISSON | EpiCARE* - Dr Andreas BRUNKLAUS | EpiCARE* - Pr Rima NABBOUT | EpiCARE*


                                * European Reference Network