Rett syndrome

Rett Syndrome Overview

  • Rett syndrome is characterized by a variety of symptoms that can include:

    • Repetitive hand movements

    • Gait abnormalities

    • Ataxia

    • Tremors

    • Seizures

  • Gastrointestinal problems are also correlated with the syndrome.

  • Traits resembling autism and other developmental disabilities may be observed.

  • Psychomotor development is typically normal for the first 6 to 18 months followed by:

    • A plateau in development

    • A steep decline afterwards.

Historical Background

  • First described in 1966 by Andreas Rett.

  • Gained attention after Bent Hinnberg's publication in 1983, establishing the condition's recognition.

  • Originally misclassified as an autism spectrum disorder.

  • The MECP2 mutation, discovered in the lab of Dr. Uda Zanko, was identified as the primary cause around 2005.

Genetic Basis

  • Rett syndrome is primarily caused by de novo mutations in the MECP2 gene, almost always occurring spontaneously during embryonic development.

  • Insufficient protein function or the production of a dysfunctional protein from these mutations leads to the disease.

  • Over 800 different types of MECP2 mutations have been identified, and mutations in other genes can cause atypical variants:

    • Congenital Rett syndrome: caused by mutations in the FOXG1 gene.

    • Early onset/hand-field variant: linked with CDKL5 mutations.

  • Common mutation types include:

    • Missense, nonsense, frameshift, and deletions.

    • Milder phenotypes are often associated with point mutations.

    • Severe mutations, especially large deletions, often result in failure to survive past infancy.

Prevalence and Survival

  • Affects approximately 1 in 10,000 to 15,000 live female births, identified across ethnic groups.

  • Males often do not survive due to factors such as:

    • Mosaicism (not all cells express the mutation)

    • X-inactivation complications in Klinefelter syndrome (XXY)

    • Variability in mutation severity.

  • MeCP2 regulates gene expression, crucial for the development of the nervous system by:

    • Silencing and activating genes involved in brain development.

    • Regulating synaptic plasticity, neuronal maturation, RNA splicing, and chromatin organization.

Clinical Phenotypes

  • The primary driver of symptoms is central nervous system disturbances, leading to:

    • Synaptic dysfunction affecting neuronal communication.

    • Potential mitochondrial and inflammatory dysfunctions as both causes and consequences.

  • Inflammation: Microglia in the CNS alter homeostasis, where MECP2 impacts T cell and macrophage function.

    • Disruptions can lead to increased inflammation.

Respiratory and Neurological Effects

  • Symptoms may include:

    • Dysphagia (swallowing difficulties)

    • Breath holding, leading to hypoxia, further complicating respiratory functions.

  • Apnea may worsen due to dysfunctional mitochondrial and redox systems.

  • Ongoing studies indicate homeostatic drivers may impact pathophysiology.

  • Dysfunction in the hippocampus and neocortex increases neuronal excitability linked to breathing issues.

Diagnosis and Treatment

  • Diagnostic options include:

    • Genome sequencing, exome analysis, gene panels, multi-gene testing, and microarrays.

  • Clinical diagnosis is possible without identifying a pathogenic variant due to evident symptoms.

  • There is currently no cure for Rett syndrome and treatment often aims at symptom management:

    • Medications can disrupt the balance of interconnected systems.

    • Therapy options include physical, occupational, and speech therapy to improve quality of life.

Longitudinal Study Findings

  • A 20-year surveillance study highlighted the health status of adults with Rett syndrome:

    • Focused on females over 18 years of age.

    • The methodology involved databases like the Australian Rett Syndrome Database and InterRett.

  • Notable findings include:

    • Respiratory illnesses: 36.8% of deaths due to lower respiratory tract infections.

    • Seizures and related illnesses contributed significantly to mortality.

    • Probability of survival decreases with age (77.6% at 20 years; 59.8% at 37 years).

  • Mutational impact:

    • 300 individuals had a pathogenic variant; large deletions associated with three times greater risk of death.

    • Epileptic conditions: 64% on antiepileptics, with a significant percentage being drug-resistant.

    • Only 17.8% were able to walk independently.

    • High prevalence of scoliosis in females (85.5%).

    • Breathing abnormalities: present in about 66.4% of subjects, with little variation across mutation types.