From the Guidelines
Rett syndrome is a neurodevelopmental disorder characterized by normal development until 4 years of age, followed by decelerated head growth, loss of purposeful hand movements, and stereotyped hand movements, primarily affecting females due to mutations in the MECP2 gene. The key features of Rett syndrome (RS) for the United States Medical Licensing Examination (USMLE) Step 1 include normal head circumference and development at birth and during infancy, with head growth decelerating before 4 years of age 1. Some of the key clinical presentations are:
- Loss of purposeful hand movements
- Characteristic stereotyped hand movements, such as wringing or washing
- Decelerated head growth
- Normal development until 4 years of age The MECP2 gene plays a central role in this disorder, and mutations in this gene can lead to differing clinical manifestations in boys, ranging from fatal encephalopathy to progressive but nonfatal developmental disorder 1. It is essential to distinguish Rett syndrome from other neurodevelopmental disorders, such as childhood disintegrative disorder (CDD) and Asperger’s disorder, which have distinct clinical features and outcomes 1. For the USMLE Step 1 exam, it is crucial to remember the classic presentation of a girl with normal early development who regresses and develops the characteristic hand-wringing movements, as this is a high-yield clinical vignette.
From the Research
Key Features of Rett Syndrome
- Rett Syndrome (RS) is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in the gene Methyl-CpG-binding protein 2 (MECP2) 2
- It is an X-linked dominant disorder, almost exclusively affecting females 3
- MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders 4
- The disorder is characterized by progressive neurological deterioration, with symptoms including mental retardation, loss of speech, and motor dysfunction 3
Genetic Underpinnings
- Nearly 80% of RS cases are sporadic, caused by mutations in the MECP2 gene located on Xq28 3
- Mutations in the MECP2 gene have been identified in more than 80% of females with typical features of Rett syndrome 5
- The most common mutation is R168X, and about 67% of all MECP2 mutations are located in the third and fourth exon 3
Clinical Manifestations
- The majority of patients with identified MECP2 mutations have the classic Rett phenotype, while some have atypical phenotypes 5
- Common clinical features include acquired microcephaly, although its absence does not obviate the need for MECP2 analysis 5
- The disorder can result in an imbalance of neuronal excitation and inhibition at the circuit level, along with dysregulation of activity-dependent mechanisms 6