Rett syndrome

Rett syndrome is a rare and severe genetic neurological disorder that predominantly affects females. It is characterized by a period of apparently normal development followed by a regression of acquired skills, loss of purposeful hand use, and the development of distinctive hand-wringing movements. The disorder leads to severe impairments, affecting nearly every aspect of the individual's life, including motor skills, speech, and cognitive function, and is a leading cause of profound intellectual disability in females.

Signs and symptoms

Initial development typically appears normal until 6 to 18 months of age, after which a regression phase begins. This stage involves a loss of purposeful hand skills, which are replaced with repetitive, stereotyped hand movements such as wringing, washing, or tapping. There is often a loss of acquired spoken language and the onset of gait abnormalities or a complete loss of ambulation. Other common features include episodes of hyperventilation, apnea during wakefulness, bruxism, and disrupted sleep patterns. Many individuals develop scoliosis, growth retardation, and autonomic dysfunction. Seizures are a frequent comorbidity, and the disorder shares some overlapping features with other neurodevelopmental conditions like autism spectrum disorder and cerebral palsy.

Causes and genetics

The primary cause is a mutation in the MECP2 gene located on the X chromosome. This gene provides instructions for making a protein essential for normal brain development, functioning as a critical regulator of other genes. Most cases arise from *de novo* mutations, meaning they are not inherited from the parents but occur spontaneously. Because females have two X chromosomes, the presence of one normal MECP2 gene moderates the severity, which is why the disorder is seen almost exclusively in girls; mutations in males are usually lethal in utero or lead to severe neonatal encephalopathy. Rare variants can be caused by mutations in other genes, such as CDKL5 and FOXG1, which cause overlapping but distinct phenotypes.

Diagnosis

Diagnosis is based on established clinical criteria, with essential features including a period of regression followed by recovery or stabilization, loss of purposeful hand skills, and the development of gait dyspraxia. Supportive criteria include breathing disturbances, bruxism, and impaired sleep. Genetic testing confirming a mutation in the MECP2 gene provides a definitive diagnosis. Differential diagnosis involves ruling out other childhood neurological disorders such as Angelman syndrome, Prader-Willi syndrome, and other causes of developmental regression. The Diagnostic and Statistical Manual of Mental Disorders includes it under neurodevelopmental disorders.

Management

There is no cure, so management is supportive, symptomatic, and multidisciplinary. Care often involves a team including neurology, pediatrics, physical therapy, occupational therapy, and spe-language pathology. Interventions focus on improving communication through augmentative and alternative communication devices, managing seizures with antiepileptic drugs like carbamazepine or lamotrigine, and treating scoliosis with bracing or surgery. Nutritional support is critical, sometimes requiring gastrostomy feeding. The Food and Drug Administration has approved the drug trofinetide for treatment. Research into gene therapy is ongoing at institutions like the National Institutes of Health.

Prognosis

The prognosis is variable but generally involves significant lifelong disability. Life expectancy is reduced, with many individuals surviving into middle age, though sudden, unexplained death, potentially related to cardiac or respiratory issues, is a risk. The trajectory often involves initial regression, a subsequent plateau or slight recovery phase, and then a period of motor deterioration later in life. The severity of symptoms, particularly respiratory problems, scoliosis, and seizure control, significantly impacts overall health and longevity. Long-term care is typically required, often in specialized facilities or with extensive in-home support.

History and epidemiology

The disorder was first described in 1966 by Austrian physician Andreas Rett after he observed two girls in his waiting room exhibiting similar hand-washing motions. His findings, published in German, gained wider recognition after a 1983 article by Bengt Hagberg and colleagues in the Annals of Neurology. It occurs worldwide in approximately 1 in 10,000 to 15,000 female births across all ethnic groups. Major advocacy and research organizations include the International Rett Syndrome Foundation and Rett Syndrome Research Trust. Awareness was significantly increased by public figures like Julia Roberts, who served as a spokesperson for a related charity. Category:Genetic disorders Category:Neurological disorders Category:Pediatrics