Rett syndrome
Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females.[4] Symptoms include impairments in language and coordination, and repetitive movements.[4] Those affected often have slower growth, difficulty walking, and a smaller head size.[4][5] Complications of Rett syndrome can include seizures, scoliosis, and sleeping problems.[4] The severity of the condition is variable.[5]
Not to be confused with Tourette syndrome.Rett syndrome
Impairments in language and coordination, and repetitive movements, slower growth, smaller head[4]
After 6–18 months of age[4]
Lifelong[5]
Based on symptoms, genetic testing[5]
Special education, physiotherapy, braces[5]
Life expectancy for many is middle age.[5]
1 in 8,500 females[4]
Lethal in males, with rare exceptions.
Rett syndrome is due to a genetic mutation in the MECP2 gene,[4] on the X chromosome.[5] It almost always occurs as a new mutation, with less than one percent of cases being inherited.[4][5] It occurs almost exclusively in girls;[4] boys who have a similar mutation typically die shortly after birth.[5] Diagnosis is based on the symptoms and can be confirmed with genetic testing.[5]
There is no known cure for Rett syndrome.[5] Treatment is directed at improving symptoms.[5] Anticonvulsants may be used to help with seizures.[5] Special education, physiotherapy, and leg braces may also be useful depending on the needs of the child.[5] Many of those with the condition live into middle age.[5]
The condition affects about 1 in 8,500 females.[4] In 1999, Lebanese-American physician Huda Zoghbi discovered the mutation that causes the condition.[7][8]
Signs and symptoms[edit]
Stage I[edit]
Stage I, called early-onset, typically begins between 6 and 18 months of age.[5] This stage is often overlooked because symptoms of the disorder may be somewhat vague, and parents and doctors may not notice the subtle slowing of development at first.[5] The infant may begin to show less eye contact and have reduced interest in toys. There may be delays in gross motor skills such as sitting or crawling.[5] Hand-wringing and decreasing head growth may occur, but not enough to draw attention. This stage usually lasts for a few months but can continue for more than a year.[5]
Stage II[edit]
Stage II, or the rapid destructive stage, usually begins between ages 1 and 4 and may last for weeks or months.[5] Its onset may be rapid or gradual as the child loses purposeful hand skills and spoken language.[5] Characteristic hand movements such as wringing, washing, clapping, or tapping, as well as repeatedly moving the hands to the mouth often begin during this stage which is called mouthing.[5] The child may hold the hands clasped behind the back or held at the sides, with random touching, grasping, and releasing.[5] The movements continue while the child is awake but disappear during sleep.[5] Breathing irregularities such as episodes of apnea and hyperventilation may occur, although breathing usually improves during sleep.[5] Some girls also display autistic-like symptoms such as loss of social interaction and communication.[5] Walking may be unsteady and initiating motor movements can be difficult. Slowed head growth is usually noticed during this stage.[5]
Stage III[edit]
Stage III, or the plateau or pseudo-stationary stage, usually begins between ages 2 and 10 and can last for years.[5] Apraxia, motor problems, and seizures are prominent during this stage.[5] However, there may be improvement in behavior, with less irritability, crying, and autistic-like features.[5] In stage III there may be more interest in the surroundings and alertness, attention span, and communication skills may improve.[5] Many girls remain in this stage for most of their lives.[5]
Stage IV[edit]
Stage IV, or the late motor deterioration stage, can last for years or decades.[5] Prominent features include reduced mobility, curvature of the spine, and muscle weakness, rigidity, spasticity, and increased muscle tone with abnormal posturing of an arm or leg.[5] Girls who were previously able to walk may stop walking.[5] Cognition, communication, or hand skills generally do not decline in stage IV.[5] Repetitive hand movements may decrease and eye gaze usually improves.[5]
Males with pathogenic MECP2 mutations usually die within the first 2 years from severe encephalopathy, unless they have one or more extra X chromosomes, or have somatic mosaicism.
Male fetuses with the disorder rarely survive to term. Because the disease-causing gene is located on the X chromosome, a female born with an MECP2 mutation on her X chromosome has another X chromosome with an ostensibly normal copy of the same gene, while a male with the mutation on his X chromosome has no other X chromosome, only a Y chromosome; thus, he has no normal gene. Without a normal gene to provide normal proteins in addition to the abnormal proteins caused by a MECP2 mutation, the XY karyotype male fetus is unable to slow the development of the disease, hence the failure of many male fetuses with a MECP2 mutation to survive to term.
Females with a MECP2 mutation, however, have a non-mutant chromosome that provides them enough normal protein to survive longer. Research shows that males with Rett syndrome may result from Klinefelter's syndrome, in which the male has an XXY karyotype.[72] Thus, a non-mutant MECP2 gene is necessary for a Rett's-affected embryo to survive in most cases, and the embryo, male or female, must have another X chromosome.
There have, however, been several cases of 46,XY karyotype males with a MECP2 mutation (associated with classical Rett syndrome in females) carried to term, who were affected by neonatal encephalopathy and died before 2 years of age.[73] The incidence of Rett syndrome in males is unknown, partly owing to the low survival of male fetuses with the Rett syndrome-associated MECP2 mutations, and partly to differences between signs caused by MECP2 mutations and those caused by Rett's.[73]
Females can live up to 40 years or more. Laboratory studies on Rett syndrome may show abnormalities such as:
A high proportion of deaths are abrupt, but most have no identifiable cause; in some instances death is the result most likely of:
History[edit]
Andreas Rett, a pediatrician in Vienna Austria, first described the condition in 1966.[5][75] As his writings were in German, they did not become widely known in the English-speaking world.[7] Bengt Hagberg, a Swedish pediatrician, published an English article in 1983 and named the condition after Rett.[7] In 1999, Lebanese-American physician Huda Zoghbi discovered the mutation that causes the condition.[7][8]
Research[edit]
Gene therapy is under study in animal models to achieve regulated expression of a normal MECP2 gene.[5] In March 2022, Taysha Gene Therapies announced that they had received Clinical Trial Application (CTA) approval from Health Canada for a clinical trial of their investigational gene therapy for adult females with Rett Syndrome.[76]