Subtle but apparent signs of disease may precede the onset of overt symptoms in children with Rett syndrome (RTT), which could serve as early diagnostic markers or help deliver interventions ahead of symptoms that may increase these children’s chances of recovery.
Accumulating evidence suggests that early after birth, patients already present detectable behavioral and physiological impairments, which challenges the belief of Rett syndrome as a late-onset clinical condition.
Data backing this idea were reviewed in the study, “Rett syndrome before regression: a time window of overlooked opportunities for diagnosis and intervention,” published in the journal Neuroscience & Biobehavioral Reviews.
Rett syndrome (RTT) is a rare, progressive neurological disorder that primarily affects females and causes severe cognitive, social, motor, and physiological impairments.
Infants do not show any symptoms at birth, developing normally for the first six to 18 months. At this point, children begin to lose previously acquired speech and motor skills, entering a phase of developmental regression.
Symptoms are subtle at first and often overlooked. They include delays in gross motor skills such as crawling or sitting and reduced eye contact. Between ages 1 and 4, a decline in speaking and purposeful hand skills are observed.
Stereotypic hand movements and breathing irregularities may also occur at this stage. Slowed head growth is another apparent symptom of Rett syndrome. The disease usually reaches a plateau between ages 2 and 10. This phase usually lasts for several years. The last stage of the disease is characterized by muscle weakness, an abnormal curvature of the spine (scoliosis), and reduced mobility.
No cure is available, and current treatments are essentially supportive and directed toward lessening specific symptoms in each patient.
Clinical diagnosis is based on the characteristic progression of the disease, because patients show an apparently normal initial development with a subsequent sudden regression. Genetic testing can also be done to look for mutations commonly associated with the disease.
However, a growing body of evidence is “[raising] doubts regarding the absence of early impairments, hence questioning the concept of regression,” researchers stated.
Here, scientists reviewed published literature addressing the pre-symptomatic stage in patients and in animal models of Rett, highlighting the alterations in behavior, physiology and brain occurring since the first months of life.
“The emerging picture delineates subtle, but reliable, impairments that precede the onset of overt symptoms whose bases are likely set up already during embryogenesis [development of an embryo],” the authors said.
Several observations support the idea that early development is not completely normal in Rett. Infants with the disease show subtle deficits in motor skills, such as a low diversity of spontaneous movements and jerky movements, impairments in fine movements of the face, arms, and hands, and arm tremors. Poor communicative gestures, low responsiveness to call, and vocalization changes have also been noted since the first months of life.
An extreme variability in the severity of those early signs probably explains in part why they generally go undetected.
In addition, physiological alterations, including problems in sleep, breathing, and sensitivity to pain, appear to be present before the onset of manifest symptoms.
Studies in mice and rats agree with these observations, showing that sensory motor development, weight, and metabolism alterations can be affected early in models of the disease.
Importantly, these apparent initial signs are accompanied by measurable changes in the brain at the early stages of development.
Slowing of head growth, considered a typical sign of developmental regression, was already found to be present during pregnancy, with a greater proportion of infants with Rett having a lower head circumference at birth.
In mouse models, reductions in the size of nerve cells (neuronal atrophy) and alterations in their shape are observable at pre-symptomatic stages, along with irregularities in the electrical activity and chemical imbalances in the brain.
Moreover, premature alterations in mitochondrial function — responsible for the production of cellular energy — and the production of lipids (fats) in the brain may be a root cause underlying Rett symptoms.
Altogether, this evidence argues for the presence of early abnormalities in the brain in infants with Rett syndrome.
According to this review, it seems that patients regress in main acquired skills, but such skills are built on underlying biological processes which are already altered soon after birth or even during embryo development.
“The use of the term regression to define this scenario appears thus questionable and somehow misleading, since it gives the erroneous perception of a “normality” which is suddenly disrupted, rather than a progressive sum of additional bugs that at some point makes the developmental program crash,” the researchers said.
While details about disease progression are still unclear, and no adequate biomarker has been found, the findings encourage the possibility of detecting early signs of altered development as a possible diagnostic marker.
Therefore, researchers call on the urgent need to clarify whether and how early alterations contribute to the full manifestation of Rett symptoms.
“A deeper knowledge on mechanisms precociously affected in RTT could indeed help identifying early markers of disease, and to translate them into clinics for early diagnosis,” the researchers said.
Future research focusing on disease origin and development “might be expected to uncover novel targets for early intervention, thus increasing the chance of a complete recovery,” they concluded.