Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in girls. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often have slower growth, difficulty walking, and a smaller head size. Complications of Rett syndrome can include seizures, scoliosis, and sleeping problems. The severity of the condition is variable. Rett syndrome is due to a genetic mutation, usually in the MECP2 gene, on the X chromosome. It almost always occurs as a new mutation, with less than one percent of cases being inherited. It occurs almost exclusively in girls; boys who have a similar mutation typically die shortly after birth. Diagnosis is based on the symptoms and can be confirmed with genetic testing. There is no known cure for Rett syndrome. Treatment is directed at improving symptoms. Anticonvulsants may be used to help with seizures. Special education, physiotherapy, and leg braces may also be useful depending on the needs of the child. Many of those with the condition live into middle age. The condition affects about 1 in 8,500 females. In 1999, Lebanese-American physician Huda Zoghbi discovered the mutation that causes the condition.
Signs and symptoms
Stage I Stage I, called early-onset, typically begins between 6 and 18 months of age. Diagnosis is by clinical observation, and stage I is often overlooked because symptoms of the disorder may be somewhat vague; parents and doctors may not notice the subtle slowing of development at first. 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. 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.
Stage II Stage II, or the rapid destructive stage, usually begins between ages 1 and 4 and may last for weeks or months. Its onset may be rapid or gradual as the child loses purposeful hand skills and spoken language. 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. The child may hold the hands clasped behind the back or held at the sides, with random touching, grasping, and releasing. The movements continue while the child is awake but disappear during sleep. Breathing irregularities such as episodes of apnea and hyperventilation may occur, although breathing usually improves during sleep. Some individuals also display autistic-like symptoms such as loss of social interaction and communication. Walking may be unsteady and initiating motor movements can be difficult. Slowed head growth is usually noticed during this stage.
Stage III Stage III, or the plateau or pseudo-stationary stage, usually begins between ages 2 and 10 and can last for years. Apraxia, motor problems, and seizures are prominent during this stage. However, there may be improvement in behavior, with less irritability, crying, and autism-resembling features. In this stage the child may be more interested in their surroundings and display increased alertness, attention span, and communication skills may improve. Many individuals with the condition remain in this stage for most of their lives.
Stage IV Stage IV, or the late motor deterioration stage, can last for years or decades. 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. Individuals who were previously able to walk may lose this ability. Cognition, communication, or hand skills generally do not decline in stage IV. Repetitive hand movements may decrease and eye gaze usually improves.
Variants The signs and symptoms of the typical form of the Rett syndrome are well described. In addition to the classical form of Rett syndrome, several atypical forms have been described over the years; the main groups are:
Congenital variant (Rolando variant, FOXG1 syndrome): in this severe subtype of Rett syndrome, the development of the patients and their head circumference are abnormal from birth. The typical gaze of Rett syndrome patients is usually absent. Due to the differences and symptoms and cause, it is often not considered a variant of Rett syndrome; Zappella variant of Rett Syndrome or preserved speech variant: in this subtype of Rett syndrome the patients acquire some manual skills and language is partially recovered around the age of 5 years (that is after the regression phase). Height, weight and head circumference are often in the normal range, and a good gross motor function can be observed. The Zappella variant is a milder form of Rett syndrome; Hanefeld variant or early epilepsy variant. In this form of Rett syndrome, the patients have epilepsy before 5 months of age. The definition itself of the Rett syndrome has been refined over the years: as the atypical forms subsist near to the classical form (Hagberg & Gillberg, 1993), the "Rett Complex" terminology has been introduced.
Cause Genetically, Rett syndrome (RTT) is often caused by mutations in the gene MECP2 located on the X chromosome (which is involved in transcriptional silencing and epigenetic regulation of methylated DNA), and can arise sporadically or from germline mutations. In less than 10% of RTT cases, mutations in the genes CDKL5 or FOXG1 have also been found to resemble it. A 2021 study by scholars based at Scottish universities states that Rett syndrome is in fact a neurodevelopmental condition as opposed to a neurodegenerative condition. One piece of evidence for this is that mice with induced Rett syndrome show no neuronal death, and some studies have suggested that their phenotypes can be partially rescued by adding functional MECP2 gene back when they are adults. This information has also helped lead to further studies aiming to treat the disorder.
Sporadic mutations In at least 95% of Rett syndrome cases, the cause is a de novo mutation in the child, almost exclusively from a de novo mutation on the male copy of the X chromosome. It is not yet known what causes the sperm to mutate, and such mutations are rare.
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