Objective:The clinical features and genetics of Rett syndrome (RTT) have been well studied, but examination of quality of life (QOL) is limited. This study describes the impact of clinical severity on QOL among female children and adolescents with classic RTT. Methods:Cross-sectional and longitudinal analyses were conducted on data collected from an NIH-sponsored RTT natural history study. More than 200 participants from 5 to 18 years of age with classic RTT finished their 2-year follow-up at the time of analysis. Regression models after adjustment for their MECP2 mutation type and age at enrollment were used to examine the association between clinical status and QOL. Results:Severe clinical impairment was highly associated with poor physical QOL, but worse motor function and earlier age at onset of RTT stereotypies were associated with better psychosocial QOL; conversely, better motor function was associated with poorer psychosocial QOL. Conclusions:Standard psychosocial QOL assessment for children and adolescents with RTT differs significantly with regard to their motor function severity. As clinical trials in RTT emerge, the Child Health Questionnaire 50 may represent one of the important outcome measures. Rett syndrome (RTT), a neurodevelopmental disorder occurring in 1 of 10,000 female births, 1-5 is characterized by apparently normal psychomotor development during the first 6 -18 months of life followed by regression (loss of purposeful hand use and spoken communication skills), social withdrawal, cognitive impairment, gait dysfunction, 6 and stereotypic hand movements, a hallmark of RTT. 7 Mutations in the methyl-CpG-binding protein 2 gene (MECP2), located at Xq28, account for approximately 95% of individuals with RTT. 8,9 Among the more than 250 different pathogenic mutations, the 8 most common point mutations account for about 60% of individuals with RTT. Small deletions in the C-terminal region of MeCP2 represent an additional 7%-9% and large-scale deletions represent 8%-10%. 10The spectrum of clinical severity for individuals with RTT correlates with specific mutations. Little is known about the impact of RTT on quality of life (QOL). In anticipation of clinical trials, it is essential to understand the applicability of a general QOL measure, particu-

Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator that binds the methyl CpG dinucleotide in target genes to regulate transcription. Previously we and others reported a role of microglia in the pathophysiology of RTT. Because microglia in the Mecp2 knockout (Mecp2KO) mouse model of RTT over-produce neurotoxic mediators glutamate and reactive oxygen species, we hypothesize that blocking neuron–microglia interaction by ablation of CX3CR1, a chemokine receptor expressed in microglia/myeloid cells mediating such interaction by pairing with its neuronal ligand CX3CL1, would ameliorate the RTT-like phenotype in Mecp2KO mice. Here we report that CX3CR1 ablation prolonged the lifespan of Mecp2KO mice from a median survival of 54.5–74 days, and significantly improved the body weight gain, symptomatic scores, major respiratory parameters, and motor coordination and performance. CX3CR1 ablation rectified previously identified histological abnormalities in the Mecp2KO brain such as neuronal soma size in hippocampal CA2, and the number, soma size, and process complexity of microglia. Moreover, CX3CR1 ablation enhanced the neurotrophic action of microglia in Mecp2KO mice by producing higher amount of insulin-like growth factor 1. Our data support a role of myeloid cells/microglia in RTT and suggest a novel therapeutic approach for RTT by targeting CX3CR1 with specific antagonists or genetic downregulation.

Osteopathia striata, an autosomal dominant disorder, has been diagnosed in a 19-year-old mildly retarded woman. In addition, she has macrocephaly, a leonine facies, disfigurement of the lower jaw, a cleft palate and mixed hearing loss. Roentgenograms of the skull and long bones show thickening of the calvarium, particularly at the base, mandibular hyperplasia, and striations in the long bones and pelvis. Except for the cleft palate, which has not been previously reported, and the retardation, which appears to be quite uncommon in this condition, these findings are characteristic of osteopathia striata. Because the disorder may resemble several other conditions, the differential diagnosis should include osteopoikilosis, the autosomal dominant form of osteopetrosis, and hyperostosis corticalis generalisata.

Rett syndrome is a severe neurodevelopmental disorder generally affecting girls. Affected individuals are apparently normal at birth but later pass through a period of regression with loss of hand and communication skills and the development of hand stereotypies and dyspraxia. Mutations in the methyl-CpG binding protein 2 (MECP2) gene, have now been found to cause Rett syndrome in up to 80% of classical cases. We report a girl with Down syndrome, one of three children with birth defects in a family of five. From the age of 18 months she developed symptomatology considered by her primary physician to be very characteristic of Rett syndrome. However, this remained a clinical diagnosis till the age of 12 years. Laboratory confirmation of the dual diagnosis, which includes a R168X mutation in the MECP2 gene in addition to trisomy 21, has now been possible. The presence of one neurological or developmental disorder does not necessarily preclude a diagnosis of Rett syndrome.

Rett syndmme -Preserved speech i So far the Norwegian series of listed females with a verified or tentative diagnosis of Rett syndrome comprises 94 individuals (October 1994). Wty-one of these have been thoroughly' assessed, both clinicaJly, neurophysiologically and biochemically. ?kro individuals did not fulfil the criteria of Rett syndrome, and were excluded. Hence, the present sample cornprises 49 females.Since early diagnosis is usually considered tentative, a l l girls included were above 2 '/2 years. The mean age was 1 ]/a ( y d m o n t h s ) and the range was 2/7-46/11, Tlmty-six of the females fulfilled the critmia of classical Rett syndrome, and 13 belong to the Reff variant group (1). Three of them were c I W e d as having the forme h t e variant with a more mdd and protracted clinical course. Six girls showed congenital o w t , two of them were sisters. Two of the females have the early onset variant, and finally two @rk have the preserved speech variant.The sample presented comprises a substantial part of the known Norwegian population of girls and women with Rett syndrome. It includes fewer than expected forme hste variants. The reasons for this may be that the delineation towards other variants can be d~£6cult to draw (e.9. towards the early seizure variant and the p& s p x h variant). Another possibility is that the age dstribution is skewed, favoring females with earlier onsets. It might also be that the forme fruste variants have a different genetic etiology than classical Rett syndrome, and therefore have a different incidence in different geographical areas.The fact that six &Is belong to the congenital variant implies that h c i a n s should be aware of Reff syndrome syrnptomatology even in girls who appeared delayed h m birth.The developmental and the present chical status of the two girls with prae.mil speech revealed symptoms and signs convincing of Rett syndrome. The speech of one of the girls, aged 16 years, is characterized by echolalia and little spontaneous use. It consists mainly of short sentences, typically repeating parts h m the same narratives, such as Winnie the Pooh, for many years. Most utterances appear in ritualized dialogues that are initiated by a partner -usually one of the parents -who facilitates the girl's speech by beghning utterances that she finishes. Although these dialogues may contain considerable variation in vocabulary use, the only genuinely self-initiated utterances are "I am hungry" and "I am thirsty".The other girl is five years old. She used several words at eight months, and long sentences before speech became sparse and was reduced to babbling mund two years of age. She started to speak again at 3 '/2 years, initially with single-word utterances, and mainly to express needs. At the age of five years she speaks in short sentences, but still only to express needs.In spite of their much larger speech repertoire than other females with Rett syndrome, the two girls with preserved speech have limited pragmatic functions, and truly spontaneous speech is mainly ...