Rett Sendromu
Özet
Rett sendromu (RS), çoğunlukla kızları etkileyen, ağır ve progresif bir nörogelişimsel bozukluktur. Vakaların büyük kısmında MECP2 genindeki patojenik varyantlar saptanır ve MeCP2 proteininin kaybı, gen ekspresyonu ile sinaptik işlevlerde yaygın bozulmalara yol açar. Klinik olarak RS; normal erken gelişim döneminin ardından konuşma, el becerileri ve motor fonksiyonlarda gerileme ile karakterizedir. Bu gerilemeyi el stereotipileri, yürüme bozuklukları, epilepsi, solunum düzensizlikleri, anksiyete ve gastrointestinal sorunlar takip eder. Nörogörüntüleme ve hayvan modelleri, beyin hacminde azalma, nöron boyutunda küçülme ve nörotransmitter dengesizliklerini göstermektedir. Güncel tedavi yaklaşımı semptomların yönetimine odaklanır; ancak MeCP2 eksikliğini hedefleyen terapötik araştırmalar hızla ilerlemektedir. IGF-1 türevi trofinetide, RS için FDA onayı alan ilk ilaçtır. Gen tedavisi ve X kromozomu inaktivasyonunu modüle etmeyi amaçlayan stratejiler ise gelecekte umut vadetmektedir.
Rett syndrome (RS) is a severe and progressive neurodevelopmental disorder that predominantly affects females and is most commonly caused by pathogenic variants in the MECP2 gene. Loss of MeCP2 disrupts gene regulation and neuronal function, leading to widespread abnormalities in synaptic development. Clinically, RS is characterized by developmental regression involving loss of spoken language, purposeful hand use, and motor abilities, followed by the emergence of hand stereotypies, gait abnormalities, epilepsy, respiratory irregularities, anxiety, and gastrointestinal dysfunction. Neuroimaging and experimental models consistently demonstrate reduced brain volume, global neuronal shrinkage, and disturbances across multiple neurotransmitter systems. Current management focuses on symptomatic treatment and prevention of complications, guided by updated natural history studies. Trofinetide, an IGF-1–related compound, is the first FDA-approved therapy for RS. Ongoing research into gene-based therapies, including MECP2 replacement and X-chromosome reactivation strategies, offers promising future directions for disease-modifying treatment.
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