Rett syndrome is a rare neurological disorder primarily affecting girls, impacting their development after an initial period of seemingly typical growth. While a common or “classic” form exists, there are also various “atypical” presentations. These atypical forms are less understood but represent a significant part of the disorder’s spectrum, involving a range of symptoms and diverse manifestations.
Understanding Rett Syndrome and Its Variations
Classic Rett syndrome is largely attributed to mutations in the MECP2 gene, located on the X chromosome. This gene provides instructions for creating a protein called MeCP2, which is involved in brain function and maintaining connections between nerve cells. Approximately 90-95% of classic Rett syndrome cases are linked to a mutation in this gene, where the mutation leads to insufficient or non-functional MeCP2 protein, disrupting normal brain development.
Atypical Rett syndrome, in contrast, encompasses a broader set of conditions that share characteristics with classic Rett syndrome but do not fulfill all its diagnostic criteria. These variations can arise from different types of MECP2 mutations or mutations in other genes entirely. Examples of other genes that can be involved include CDKL5 and FOXG1, which are associated with specific atypical variants.
The severity and progression of symptoms in atypical forms can be diverse, ranging from milder presentations to more severe outcomes than classic Rett syndrome. This variability often stems from the specific genetic mutation involved and how it affects the MeCP2 protein or other related proteins.
Recognizing Symptoms and Diagnostic Approaches
Individuals with atypical Rett syndrome display a range of symptoms varying in presentation and severity. Common features include difficulties with purposeful hand use, challenges in spoken communication, and problems with motor skills, such as walking. Many individuals also experience repetitive hand movements, often described as wringing, clapping, or mouthing.
Co-occurring conditions are also common, with breathing irregularities, sleep disturbances, and seizures frequently observed. Other symptoms can include teeth grinding, abnormal muscle tone, growth issues, cold extremities, and episodes of inappropriate laughing or screaming. Some individuals may also exhibit intense eye communication, using their gaze to convey messages.
Diagnosis of atypical Rett syndrome relies primarily on clinical observation and a thorough review of medical history. A period of developmental regression followed by stabilization or recovery is a diagnostic requirement. For a diagnosis of atypical Rett syndrome, an individual meets at least two of the four main criteria for classic Rett syndrome and at least five of eleven supportive criteria.
Genetic testing, particularly for the MECP2 gene, serves as a supportive tool in the diagnostic process. However, a negative MECP2 genetic test does not exclude a diagnosis of atypical Rett syndrome, as other genes or different MECP2 mutations can be responsible. Broader genetic panels that include genes like CDKL5 and FOXG1 may also be used to identify other genetic causes.
Exploring Atypical Rett Syndrome Subtypes
Several distinct subtypes of atypical Rett syndrome have been identified, each with unique characteristics. These subtypes highlight the broad spectrum of the disorder.
One such subtype is the preserved speech variant, also known as the Zappella variant. Individuals with this variant may retain or recover some speech and language abilities, a notable deviation from the characteristic loss of speech seen in classic Rett syndrome. They may also show improvements in purposeful hand movements.
The congenital variant, or Rolando variant, is considered a more severe form, with the onset of classic Rett features occurring very early in life, often within the first three months. Conversely, the early-onset seizure variant, or Hanefeld variant, is characterized by seizures in the first few months of life, followed by the development of other Rett syndrome features. This variant is often linked to mutations in the CDKL5 gene.
Another subtype is the late childhood regression variant, where regression in language and motor skills occurs later in childhood, around 36 months, and is more gradual. Individuals with this variant often have a normal head circumference. The forme fruste variant is a milder presentation with symptoms appearing in early childhood, and individuals may not develop all the symptoms seen in classic Rett syndrome.
Managing and Supporting Individuals
Managing atypical Rett syndrome involves a comprehensive, multidisciplinary approach focused on addressing symptoms and enhancing quality of life. Various therapeutic interventions are employed to support development and functional abilities.
Physical therapy is often used to maintain mobility, improve posture, and manage gait abnormalities. Occupational therapy helps individuals develop and maintain skills for daily living, such as feeding and dressing. Speech and communication therapy is also important, often incorporating augmentative and alternative communication (AAC) methods, including eye-gaze devices, to facilitate expression.
Nutritional support is a common consideration due to potential feeding difficulties and growth retardation. Medications may be prescribed to manage specific symptoms like seizures, sleep disturbances, or gastrointestinal issues. The FDA approved trofinetide (Daybue) in March 2023, as the first treatment specifically for Rett syndrome, indicated for individuals aged 2 years and older. Ongoing support for individuals and their families, including access to specialized care and community resources, remains an important aspect of long-term management.