Rett syndrome: a seminal book on extensive multidisciplinary analyses for rare disease

Abstract

This book is unique in its overall broad spectrum describing RETT syndrome (RTT) from the history of its identification to the detailed clinical, communication, cog-nitive and behavioral features, their temporal evolution, its medical and surgical management, molecular genetics, research findings leading to therapeutic trials, and including a parental experience description. As such, this precious compendium skillfully crafted by 40 expert authors led by five editors can be thought of as a model for the comprehensive approach needed for rare disease syndrome management by professionals in pediatrics, neurosciences, genetics, physiology, physiotherapy, rehabilitation, and drug discovery. After reviewing the vast contribution of Andreas Rett in the identification of a neurodevelopmental disorder affecting girls with a halt in the development and hand stereo-typies, initially mistakenly thought to be linked to hyperammonemia in 1966 and 1977, followed by the seminal paper of Bengt Hagberg, Jean Aicardi et al. describing a large series of 35 girls with loss of purposeful hand movements in 1983 leading to the successive consensus diagnostic criteria of 1998, 2001a (Kerr et al.), and finally 2010 by Jeffrey Neul et al. These clinical expert syndrome delineations were comforted by the identification of the MECP2 causal gene by Amir et al in 1999, followed by the identification of the variant RTT-associated genes, CDKL5 and FOXG1. The current diagnostic description emphasizes the dynamic temporal evolution of RTT, with five phases of normal development for 6-18 months, development arrest, regression of social contact and finger skills, stabilization with better social contact, and eye gaze by age 5 in most, and thereafter effective social interaction with gradual slowing of motor functions through adulthood. The consensus diagnostic criteria, which should be considered in girls with a period of regression, followed by recovery or stabilization include two of the four main criteria and five of the 11 supportive criteria, and exclusion of traumatic brain injury and grossly abnormal development before 6 months (lack of head control, swallowing or social smile). The main criteria includes loss of purposeful hand skills or acquired spoken language, gait abnormalities, and stereotypic hand movements. Supportive criteria include awake breathing anomaly or bruxism, sleep pattern, muscle tone, peripheral vasomotor, kyphoscoliosis, short stature, small cold hands and feet, laughing/screaming spells, and intense eye communication. The book clearly describes the difference between "classical RTT"associated with MECP2 mutations in over 90% versus the variant forms of "preserved speech" also mostly linked to MECP2, while the "early seizure" variant should prompt genotyping of CDLK5, and the congenital variant is mostly associated with FOXG1 mutations. The evaluation of cognition, communication, and behavior skills are described in detail, with a particular discussion of adequate tools for assessment in persons with altered speech and development. The structure of MECP2 is discussed in detail with methylated-CpG-binding domain harboring 65% of pathogenic amino acid substitutions, while eight C to T transitions at hotspots account for 70% of the mutations found in RTT, 7-12% are small insertions/deletions found in the C-terminal domain, and 7% are large deletions. Use of mutation-type to assess the severity is discouraged, even