Giorgio Pini

Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females

Abstract. Rett syndrome is an X-linked dominant neurological disorder, which appears to be the commonest genetic cause of profound combined intellectual and physical disability in Caucasian females. Recently, this syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of still unknown target genes. Here we report a detailed mutational analysis of 62 patients from UK and Italian archives, representing the first comparative study among different populations and one of the largest number of cases so far analyzed. We review the literature on MECP2 mutations in Rett syndrome. This analysis has permitted us to produce a map of the recurrent mutations identified in this and previous studies. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, which is conserved among brain-specific regulatory factors.

Changing the perspective on early development of Rett syndrome.

Highlights ► Our study provides new insights into the pre-regressional development of RTT. ► The pre-regression period should not be considered asymptomatic. ► Peculiarities in speech-language development are potential red flags for RTT.

Cardiorespiratory challenges in Rett's syndrome

www.thelancet.com Vol 371 June 14, 2008 1981 Rett’s syndrome is a genetic neurodevelopmental disorder with brainstem immaturity that aff ects one in 10 000 women. The condition shows the importance of the brainstem in cardiorespiratory medicine. There is a lack of understanding of the cardiorespiratory disturbance in the disorder within the medical community, which makes management a challenge. Therefore an international group of experienced medical practitioners from various disciplines gathered in the Swedish National Rett Centre, Frösön, to collate their experience on Rett’s syndrome and provide a practical management strategy for all health-care tiers: the Frösö Declaration. The six cardinal features of Rett’s syndrome (table) are age-dependent. Abnormalities become evident during the fi rst or second year of life. A regression stage, characterised by an exacerbation of brainstem features, usually seems to take place in the second year. There is poor parasympathetic development, leading to a unique sympathovagal imbalance with the misleading impression of sympathetic overactivity. A lack of integrative inhibitions in the brainstem pre vents appropriate cardiovascular regulation during abnor mal breathing, causing an increased risk of adverse cardiorespiratory events. Brainstem disorders are the main reasons to seek urgent medical atten tion in Rett’s syndrome throughout life. Multiorgan involvement of in breathing-related metabolic disorders needs professional care and includes cardiologists, anaesthetists, respiratory physicians, endocrinologists, nutritionists, neurologists, paediatricians, and general practitioners. Early diagnosis to avoid long-term medical uncertainty is the primary aim. A search for mutations in the MECP2 gene in infants with unexplained developmental slurring is recommended. Then the cardiorespiratory phenotype should be established at the onset of brainstem disorders, because each of the three phenotypes is unique and needs a specifi cally tailored management strategy. Establishing the cardiorespiratory phenotype requires detailed neurophysiology. The primary pathophysiology is a defective control mechanism of carbon dioxide exhalation that leads to respiratory alkalosis or acidosis. Patients with phenotype 1 are forceful breathers who usually have fi xed low concentrations of partial pressure of carbon dixoide (pCO2), causing chronic respiratory alka losis. To interrupt an episode of forceful breathing, we recom mend fi rst re-breathing into a 5-L bag attached Cardiorespiratory challenges in Rett’s syndrome two-thirds of Tibetan people have not had access to iodised salt. Despite the overall poor coverage, the picture is not all bleak. In Tibet, there are 890 primary schools, 118 middle schools, and 1568 teaching. Of the 470 000 students attending these schools, three-quarters eat in school dining halls 5 days a week. Happily, all school dining halls in Tibet use iodised salt in accordance with a policy and schools health-promotion programme set out by the Education Bureau of Tibet in 2005. Since then, around 350 000 school children consume iodised salt at least 5 days a week, thus achieving the required intake of iodine for children.

IGF1 as a Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients

Rett syndrome (RTT) is a devastating neurodevelopmental disorder that affects one in ten thousand girls and has no cure. The majority of RTT patients display mutations in the gene that codes for the methyl-CpG-binding protein 2 (MeCP2). Clinical observations and neurobiological analysis of mouse models suggest that defects in the expression of MeCP2 protein compromise the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function, such as insulin-like growth factor 1 (IGF1), are good candidates for ameliorating the symptoms of RTT. IGF1 and its active peptide, (1–3) IGF1, cross the blood brain barrier, and (1–3) IGF1 ameliorates the symptoms of RTT in a mouse model of the disease; therefore they are ideal treatments for neurodevelopmental disorders, including RTT. We performed a pilot study to establish whether there are major risks associated with IGF1 administration in RTT patients. Six young girls with classic RTT received IGF1 subcutaneous injections twice a day for six months, and they were regularly monitored by their primary care physicians and by the unit for RTT in Versilia Hospital (Italy). This study shows that there are no risks associated with IGF1 administration.

Early speech-language development in females with Rett syndrome: focusing on the preserved speech variant.

Aim  Our aim was to contribute new findings related to the pre‐regressional verbal development of females with a variant of Rett syndrome (RTT) as the loss of spoken language is one of the key clinical features of RTT, and it would be of particular interest to study the early speech–language development of females who are considered to have preserved some speech–language abilities.

MECP2 gene mutation analysis in the British and Italian Rett Syndrome patients: hot spot map of the most recurrent mutations and bioinformatic analysis of a new MECP2 conserved region

Rett syndrome (RTT) is an X-linked dominant neurological disorder, which appears to be the most common genetic cause of profound combined intellectual and physical disability in Caucasian females. This syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of unknown target genes. We report a detailed mutational analysis of a large cohort of RTT patients from the UK and Italy. This study has permitted us to produce a hot spot map of the mutations identified. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, conserved among brain-specific regulatory factors.

Profiling Early Socio-Communicative Development in Five Young Girls with the Preserved Speech Variant of Rett Syndrome.

Highlights ► Various body movements, facial expressions, eye movements, and vocalizations were used to communicate. ► Non-verbal communicative forms dominated over verbal-communicative forms for most communicative functions. ► Early peculiarities in the speech-language domain during the first year of life became more prominent and evident during the second year of life. ► Socio-communicative deficits are present before regression and persist after this period. ► Assessing socio-communicative forms and functions at early age in children with RTT might essentially contribute to early detection.

Rett syndrome in Northern Tuscany (Italy): family tree studies

Four cases of Rett syndrome were ascertained among 19 060 girls born between 1978 and 1990 in a small, defined area of Northern Tuscany (Italy) (prevalence rate of 2.1 per 10 000). A fifth girl with a reported clinical picture of Rett syndrome, born in 1978 and deceased at age 13, was also found. One of the four Rett syndrome cases had a healthy female dizygote twin. Family tree studies going back as far as the 17th century were performed. A number of common ancestors were found in different generations leading to a single family tree encompassing all four Rett syndrome cases. In addition, a Rett girl with preserved speech, born in 1974. was found as part of this family tree. These observations confirm the role of genetic factors in the etiology of Rett syndrome and support the hypothesis that Rett syndrome is a clinically variable phenotype.

Variant of rett syndrome and CDKL5 gene: Clinical and autonomic description of 10 cases

UNLABELLED Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS In recent years more than 60 patients with mutations in the CDKL5 gene have been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. METHODS 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all subjects an evaluation of the autonomic system was performed using the Neuroscope. RESULTS Common features were gaze avoidance, repetitive head movements and hand stereotypies. The autonomic evaluation disclosed eight cases with the Forceful breather cardiorespiratory phenotype and two cases with the Apneustic breather phenotype. CONCLUSIONS The clinical picture remains within the RTT spectrum but some symptoms are more pronounced in addition to the very early onset of seizures. The cardiorespiratory phenotype was dominated by Forceful breathers, while Feeble breathers were not found, differently from the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant.

Illness Severity, Social and Cognitive Ability, and EEG Analysis of Ten Patients with Rett Syndrome Treated with Mecasermin (Recombinant Human IGF-1)

Rett Syndrome (RTT) is a severe neurodevelopmental disorder characterized by an apparently normal development followed by an arrest and subsequent regression of cognitive and psychomotor abilities. At present, RTT has no definitive cure and the treatment of RTT represents a largely unmet clinical need. Following partial elucidation of the underlying neurobiology of RTT, a new treatment has been proposed, Mecasermin (recombinant human Insulin-Like Growth Factor 1), which, in addition to impressive evidence from preclinical murine models of RTT, has demonstrated safety in human studies of patients with RTT. The present clinical study examines the disease severity as assessed by clinicians (International Scoring System: ISS), social and cognitive ability assessed by two blinded, independent observers (RSS: Rett Severity Score), and changes in brain activity (EEG) parameters of ten patients with classic RTT and ten untreated patients matched for age and clinical severity. Significant improvement in both the ISS (p = 0.0106) and RSS (p = 0.0274) was found in patients treated with IGF1 in comparison to untreated patients. Analysis of the novel RSS also suggests that patients treated with IGF1 have a greater endurance to social and cognitive testing. The present clinical study adds significant preliminary evidence for the use of IGF-1 in the treatment of RTT and other disorders of the autism spectrum.