Jana von Hehn, PhD, Chief Scientific Officer of the Rett Syndrome Research Trust, discusses the challenges of diagnosing Rett syndrome.
Rett syndrome is a multisystem disorder that primarily affects girls. Only in rare cases are boys affected (who may experience more severe symptoms). Multiple loss-of-function mutations to the MECP2 gene are the cause of Rett syndrome.
Confidently diagnosing Rett syndrome in patients younger than 2 years of age may be challenging; again, the symptom profile is highly variable. The average age of patients with typical Rett syndrome at the time of diagnosis is 2.5 years; however, as genetic testing becomes more prevalent, earlier diagnostic confirmation may be possible in the future. The average age of diagnosis for patients with atypical Rett syndrome is 3.8 years.
Since the mutations are not inherited, family history does not play a role in diagnosis. Rather, it is based almost solely on presentation and recognition of the symptomatic pattern. The first sign is the loss of previously acquired skills (also referred to as developmental regression), followed by recovery or stabilization for a time: the absence of purposeful hand movements, motor skills, and the ability to communicate. The other regression of clinical earliest signs are loss of acquired speech and motor skills, repetitive hand movements, breathing irregularities, and seizures.
Two specific criteria can exclude a diagnosis of Rett syndrome (typical or atypical): (1) brain injury secondary to trauma (peri-or postnatally), neurometabolic disease, or severe infection causing neurologic problems and (2) grossly abnormal psychomotor development in the first 6 months of life.
The differential diagnosis includes Angelman syndrome, a rare genetic and neurological disorder characterized by severe developmental delays and learning disabilities, ataxia, and absence or near absence of speech. In some rare cases, boys with neurodevelopment disorders are found upon testing to have MECP2 mutations. These cases of “male RTT encephalopathy” have symptoms distinct from typical or atypical Rett syndrome and may also be linked to other distinct disorders, such as MECP2 duplication syndrome (characterized by developmental disability, poor muscle tone, poor or absent speech), CDKL5 deficiency disorder (causing seizures, inability to speak, motor dysfunction), or FOXG1 syndrome (which has sufficient clinical similarities to have previously been classified as a “congenital variant” of Rett syndrome).
For more information about Rett syndrome, visit our Rett Syndrome Learning page here: https://checkrare.com/rett-syndrome/