Incidence and Prevalence

Global Prevalence and Incidence of Rett Syndrome

Rett syndrome is a neurodevelopmental disorder that predominantly affects females worldwide, with varying prevalence rates across different regions. As a X-linked dominant neurodevelopmental disorder, it represents the second most common cause of severe mental retardation in females after Down syndrome.

Global Prevalence

The most recent data from 2022 indicates that Rett syndrome has a prevalence rate of 1:9000 in females. Globally, it affects 1 in 10,000 to 15,000 females worldwide according to data from 2000. More specifically, it affects approximately 1 in 10,000 live female births as reported in 2015.

Regional Variations

Significant regional differences in prevalence have been documented:

• Norway (1997): A higher prevalence rate of 2.17 per 10,000 girls aged 3-19 years

• The Norwegian county of Rogaland showed an unusually high prevalence of 3.77 per 10,000 girls

• Two other Norwegian counties showed rates of 1.05 and 0.77 per 10,000 girls

• The high prevalence in Rogaland was attributed to possible genetic clustering due to limited geographical mobility

• Sweden (1991): The prevalence for classic Rett syndrome was 1:12,000-13,000 girls for birth years 1965-76 and 1960-84

• Studies from Sweden suggested that among girls the prevalence of Rett syndrome may be twice the prevalence of phenylketonuria

• Hong Kong (2008): The prevalence among female Chinese younger than 35 years was 0.57 per 10,000 (95% confidence interval, 0.15-0.98)

• Australia (2006): The prevalence was 0.88 per 10,000 females in 5- to 18-year-olds, with a cumulative incidence of 1.09 per 10,000 females by 12 years of age

• Japan:

• Tokushima prefecture (1989): 0.36/10,000 girls at age 15 and under (0.37/10,000 girls at 7-15 years)

• Tokyo (1989): 0.50/10,000 girls aged 6-14 years, including variants

• Fukui prefecture (1995): 0.22 per 10,000 girls aged 6-14 years

• These rates were lower than European studies at that time

• Texas, USA (1993): 1 per 22,800 (0.44/10,000) females aged 2 through 18 years, described as "less frequently than previously estimated"

• The Texas Rett Syndrome Registry provided the first prevalence figures for black and Hispanic female cases

Genetic Basis

The mutation of the methyl-CpG-binding protein 2 gene (MECP2) is present in up to 96% of patients with Rett syndrome. While most Rett syndrome cases are sporadic, there are documented cases of familial occurrences, indicating a genetic basis for the disorder. The Korean population shows a consistent variation spectrum with those from other ethnicities (2022).

Survival Rates

The survival rate for individuals with Rett syndrome was reported to be 100.0% at 10 years and 87.5% at 25 years based on the 2008 Hong Kong study.

Currently, there is no cure or effective therapy for Rett syndrome, with treatment regimens limited to supportive management of specific physical and mental disabilities.

Study Design Parameters

Study Design Parameters and Endpoints in Rett Syndrome Trials

Diagnostic Approaches

• Definitive diagnosis based on clinical criteria as there is no biological marker
• Diagnosis involves developmental history, cognitive function tests, and assessment of language skills
• Neuroimaging studies explore disease-specific features and genotype-phenotype associations

Assessment Parameters

• Neuroimaging: MRI morphologic studies show global atrophy; Diffusion tensor imaging demonstrates reduced fractional anisotropy
• Electrophysiological: Auditory evoked potentials and EEG testing with evoked potential studies quantify neural function
• Biochemical Markers: Paraoxonase-1 and lipoprotein-associated phospholipase A activities measured as novel candidate biomarkers

Clinical Severity Scales

• MECPDup scale developed for MECP2 duplication syndrome
• Pineda Severity score and Kerr profile scores measure clinical severity
• Clinical Global Impression Scale used as outcome measure with proposed Rett-specific anchors
• Quality of life (QoL) assessed as an independent outcome measure

Key Clinical Trials

• LAVENDER and LILAC studies (2024) of trofinetide:

• Primary endpoint: long-term safety

• Secondary endpoints: change in Rett Syndrome Behaviour Questionnaire score and Clinical Global Impression-Improvement score

• Safety assessment: treatment-emergent adverse events (TEAEs)

• Phase 1 trofinetide study (2024):

• Safety and tolerability assessed through TEAEs

• Monitoring of clinical laboratory parameters, vital signs, physical findings, and electrocardiogram results

• Dextromethorphan study (2017):

• Interictal spike activity and clinical seizures determined using EEG

• Cognitive data obtained using Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales

• Behavioral data from Aberrant Behavior Checklist-Community Version

• Rett Syndrome Severity Scale provided clinical global impression

• Glatiramer acetate studies (2011):

• Efficacy assessed by measuring BDNF expression levels in cortical areas of Mecp2 mutated mouse brain

• AAV/MECP2 gene therapy studies (2018):

• Survival extension of RTT mice as consistent outcome measure

• Toxicity assessments identified dose-dependent side effects

• Safety monitoring focused on supraphysiological expression of exogenous MeCP2

Study Populations

• A 2022 study examining auditory evoked potentials included 18 RTT participants and 27 age-matched controls between ages 6-22 years
• A 2010 study used 32 patients with RTT and 37 age-matched healthy female control subjects
• A 2004 Brazilian study included 33 female patients with chronic encephalopathy, with Rett syndrome diagnosed in 24 patients (72.7%)

Innovative Approaches

• Small data paradigm with model-informed approaches for rare disease populations
• Multimodal/multisequence studies with improved post-processing technologies
• Combined PET-MRI approaches to explore RTT brain alterations