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Neurology. 2012 Oct 16;79(16):1653-61. doi: 10.1212/WNL.0b013e31826e9a70. Epub 2012 Oct 3.

Growth failure and outcome in Rett syndrome: specific growth references.

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Tarquinio DC, Motil KJ, Hou W, Lee HS, Glaze DG, Skinner SA, Neul JL, Annese F, McNair L, Barrish JO, Geerts SP, Lane JB, Percy AK.

Source: Miami Children's Hospital, Miami, FL, USA. danieltarq@aol.com

Abstract

OBJECTIVES: Prominent growth failure typifies Rett syndrome (RTT). Our aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children with RTT with that of unaffected children, and 3) compare growth patterns among RTT genotypes and phenotypes.

METHODS: A cohort of the RTT Rare Diseases Clinical Research Network observational study participants was recruited, and cross-sectional and longitudinal growth data and comprehensive clinical information were collected. A reliability study confirmed interobserver consistency. Reference curves for height, weight, head circumference, and body mass index (BMI), generated using a semiparametric model with goodness-of-fit tests, were compared with normative values using Student's t test adjusted for multiple comparisons. Genotype and phenotype subgroups were compared using analysis of variance and linear regression.

RESULTS: Growth charts for classic and atypical RTT were created from 9,749 observations of 816 female participants. Mean growth in classic RTT decreased below that for the normative population at 1 month for head circumference, 6 months for weight, and 17 months for length. Mean BMI was similar in those with RTT and the normative population. Pubertal increases in height and weight were absent in classic RTT. Classic RTT was associated with more growth failure than atypical RTT. In classic RTT, poor growth was associated with worse development, higher disease severity, and certain MECP2 mutations (pre-C-terminal truncation, large deletion, T158M, R168X, R255X, and R270X).

CONCLUSIONS: RTT-specific growth references will allow effective screening for disease and treatment monitoring. Growth failure occurs less frequently in girls with RTT with better development, less morbidity typically associated with RTT, and late truncation mutations.
PMID:23035069  [PubMed - indexed for MEDLINE]  PMCID: PMC3468773 [Available on 2013/10/16]


 

Eur J Hum Genet. 2012 Sep 12. doi: 10.1038/ejhg.2012.208. [Epub ahead of print]

14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype.

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Ellaway CJ, Ho G, Bettella E, Knapman A, Collins F, Hackett A, McKenzie F, Darmanian A, Peters GB, Fagan K, Christodoulou J.

Source  1] Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, New South Wales, Australia [2] Disciplines of Paediatrics and Child Health and Genetic Medicine, Sydney Medical School, University of Sydney, New South Wales, Australia.

Abstract
Rett syndrome is a clinically defined neurodevelopmental disorder almost exclusively affecting females. Usually sporadic, Rett syndrome is caused by mutations in the X-linked MECP2 gene in ∼90-95% of classic cases and 40-60% of individuals with atypical Rett syndrome. Mutations in the CDKL5 gene have been associated with the early-onset seizure variant of Rett syndrome and mutations in FOXG1 have been associated with the congenital Rett syndrome variant. We report the clinical features and array CGH findings of three atypical Rett syndrome patients who had severe intellectual impairment, early-onset developmental delay, postnatal microcephaly and hypotonia. In addition, the females had a seizure disorder, agenesis of the corpus callosum and subtle dysmorphism. All three were found to have an interstitial deletion of 14q12. The deleted region in common included the PRKD1 gene but not the FOXG1 gene. Gene expression analysis suggested a decrease in FOXG1 levels in two of the patients. Screening of 32 atypical Rett syndrome patients did not identify any pathogenic mutations in the PRKD1 gene, although a previously reported frameshift mutation affecting FOXG1 (c.256dupC, p.Gln86ProfsX35) was identified in a patient with the congenital Rett syndrome variant. There is phenotypic overlap between congenital Rett syndrome variants with FOXG1 mutations and the clinical presentation of our three patients with this 14q12 microdeletion, not encompassing the FOXG1 gene. We propose that the primary defect in these patients is misregulation of the FOXG1 gene rather than a primary abnormality of PRKD1.European Journal of Human Genetics advance online publication, 12 September 2012; doi:10.1038/ejhg.2012.208.
PMID: 22968132 [PubMed - as supplied by publisher]


 

Dis Model Mech. 2012 Nov;5(6):733-45. doi: 10.1242/dmm.011007.

Preclinical research in Rett syndrome: setting the foundation for translational success.

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Katz DM, Berger-Sweeney JE, Eubanks JH, Justice MJ, Neul JL, Pozzo-Miller L, Blue ME, Christian D, Crawley JN, Giustetto M, Guy J, Howell CJ, Kron M, Nelson SB, Samaco RC, Schaevitz LR, St Hillaire-Clarke C, Young JL, Zoghbi HY, Mamounas LA.

Source

Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44120, USA. david.katz@case.edu

Abstract

In September of 2011, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the International Rett Syndrome Foundation (IRSF) and the Rett Syndrome Research Trust (RSRT) convened a workshop involving a broad cross-section of basic scientists, clinicians and representatives from the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), the pharmaceutical industry and private foundations to assess the state of the art in animal studies of Rett syndrome (RTT). The aim of the workshop was to identify crucial knowledge gaps and to suggest scientific priorities and best practices for the use of animal models in preclinical evaluation of potential new RTT therapeutics. This review summarizes outcomes from the workshop and extensive follow-up discussions among participants, and includes: (1) a comprehensive summary of the physiological and behavioral phenotypes of RTT mouse models to date, and areas in which further phenotypic analyses are required to enhance the utility of these models for translational studies; (2) discussion of the impact of genetic differences among mouse models, and methodological differences among laboratories, on the expression and analysis, respectively, of phenotypic traits; and (3) definitions of the standards that the community of RTT researchers can implement for rigorous preclinical study design and transparent reporting to ensure that decisions to initiate costly clinical trials are grounded in reliable preclinical data.
PMID: 23115203 [PubMed - in process]  PMCID: PMC3484856  Free PMC Article


 

Eur J Hum Genet. 2012 Aug 8. doi: 10.1038/ejhg.2012.156. [Epub ahead of print]

The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy.

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Fehr S, Wilson M, Downs J, Williams S, Murgia A, Sartori S, Vecchi M, Ho G, Polli R, Psoni S, Bao X, de Klerk N, Leonard H, Christodoulou J.

Source:  Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.

Abstract

The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant.European Journal of Human Genetics advance online publication, 8 August 2012; doi:10.1038/ejhg.2012.156.


 

Rett syndrome (RTT) is a neurodevelopmental disorder with one principal phenotype and several distinct, atypical variants (Zappella, early seizure onset and congenital variants). Mutations in MECP2 are found in most cases of classic RTT but at least two additional genes, CDKL5 and FOXG1, can underlie some (usually variant) cases. There is only limited correlation between genotype and phenotype. The Rett Networked Database (http://www.rettdatabasenetwork.org/) has been established to share clinical and genetic information. Through an "adaptor" process of data harmonization, a set of 293 clinical items and 16 genetic items was generated; 62 clinical and 7 genetic items constitute the core dataset; 23 clinical items contain longitudinal information. The database contains information on 1838 patients from 11 countries (December 2011), with or without mutations in known genes. These numbers can expand indefinitely. Data are entered by a clinician in each center who supervises accuracy. This network was constructed to make available pooled international data for the study of RTT natural history and genotype-phenotype correlation and to indicate the proportion of patients with specific clinical features and mutations. We expect that the network will serve for the recruitment of patients into clinical trials and for developing quality measures to drive up standards of medical management.


 

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.

METHOD:
minutes of audio-video recordings containing play situations We analysed 461 and the daily routines of six females months; mean birthweight 3057g, SD (aged 7 to 24 195g) with the preserved speech variant (PSV) of RTT. All videos were recorded by parents and analysed retrospectively after the diagnosis PSV was made.

RESULTS:
months onwards, we observed two types of vocalizations, From the age of 7 appearing intermittently: (1) apparently normal sequences; and (2) atypical (i.e. inhalatory, pressed, or high-pitched crying-like) vocalizations. Some participants failed to reach the milestone of canonical babbling. We observed a limited phonological and lexical complexity and a restricted compositional variability. Volubility was reduced during the whole period under observation. Hand stereotypies with simultaneous atypical vocalizations appeared only during the second year of life.

INTERPRETATION:
The intermittent character of normal versus abnormal verbal behaviours might contribute to an early identification of children with a possible genetic mutation, and provides evidence that speech-language functions are abnormal from the very beginning.



World Rett Syndrome Congress The Seventh

World Rett Syndrome Congress, Charting the Course, will be held June 22-26, 2012 in New Orleans. The World Congress is the largest international meeting focused exclusively on Rett Syndrome. The meeting, which takes place every four years, brings together the luminaries in the field of Rett syndrome research together with clinicians, families and a host of advocacy groups, dignitaries and other observers with an interest in learning more about the disease. And add link to http://worldcongress.rettsyndrome.org/.

New Diagnostic Criteria for Autism Spectrum Disorders

Recent media reports have raised concerns about the impact of the new diagnostic criteria for autism spectrum disorders, proposed in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to be published in May 2013, on the proportion of affected individuals who will receive the diagnosis and their access to services. The members of the DSM-5 committee responsible for these revised diagnostic criteria, which include the Chair of RettSearch, disagree with the reports on the basis of multiple sources of scientific data that most recently include field trials (i.e., real life testing of the criteria). The majority of individuals who meet DSM-IV criteria for an autism spectrum disorder will receive the DSM-5 diagnosis of autism spectrum disorder. Regardless, the media discussion on DSM-5 does not involve the changes to Rett syndrome. To reiterate the DSM-5 changes to Rett syndrome in DSM-5: when criteria are met, patients will receive the diagnosis of autism spectrum disorder associated with either Rett syndrome or MECP2 (or any other appropriate gene) mutation. There will be no unique DSM-5 diagnostic category for Rett syndrome or any other genetic disorder.

NIH/NINDS now accepting NeuroNEXT applications from investigators considering Phase II trials in neurology/neurosurgery

RettSearch members who might be considering a Phase II trial in neurology and/or neurosurgery are invited to apply to NeuroNEXT. The first receipt date is December 2, 2011. There are three mechanisms available for potential applicants

  1. Academic investigators may apply for cooperative agreement grants: NeuroNEXT Clinical Trials (U01)
  2. Small businesses may apply for cooperative agreement grants NeuroNEXT Clinical Trials (U01) or through our Small Business program NeuroNEXT Small Business Innovation in Clinical Trials (U44)
  3. Industry may apply for cooperative agreement grants NeuroNEXT Clinical Trials (U01) or apply for expedited access to the NeuroNEXT expertise and infrastructure through NeuroNEXT Infrastructure Resource Access (X01)

Please contact Elizabeth McNeil (mcneilde@ninds.nih.gov) to discuss your proposals or answer any questions about the program.

Natural History Study

RettSearch would like to announce that Annals of Neurology has published "Rett syndrome diagnostic criteria: Lessons from the Natural History Study" online. RettSearch members can access the article itself by navigating to the literature library.

Revised Diagnostic Criteria

RettSearch would like to announce that Annals of Neurology has published "Rett Syndrome: Revised Diagnostic Criteria and Nomenclature" online. RettSearch members can access the article itself by navigating to the literature library. The criteria have also been organized into two tables, which can be accessed by clicking on the links below. Please click here, or go to the "Revised Diagnostic Criteria 2010" link on the "Info for Clinicians" page, for more information about this article.

Revised Diagnostic Criteria for Rett Syndrome (RTT)

Specific variant forms of RTT

New RettSearch Library

RettSearch's library has been improved, and it is available to all members. Here you will find PDF's of scholarly articles related to Rett syndrome in a fully searchable database. We are continuing to update this library.

DSM-5 and Rett syndrome

The proposed revisions to the Diagnostic and Statistical Manual of Mental Disorders

(DSM-5) guidelines, to be released in May 2013, are currently in a feedback period until April 20th. During this period, clinicians, researchers, and affected individuals and families can provide comments. For this reason, it is important to clarify how the proposed changes will affect Rett syndrome:

  1. The current guidelines (DSM-IV) list Rett syndrome as one of four specific Pervasive Developmental Disorders, a term that refers to autistic disorders.
  2. Under the new guidelines (DSM-5), Rett syndrome will not be a specific autistic disorder. An individual with Rett syndrome and autistic disorder will be diagnosed as "Autism Spectrum Disorder associated with MECP2 mutations (or associated with Rett syndrome)".
  3. These changes were based on an exhaustive review of the literature and the consideration that Rett syndrome is not different from fragile X syndrome or other genetic disorders, in terms of its relationship with autism.
  4. Thus, an individual with Rett syndrome who does not meet criteria for Autism Spectrum Disorder will not receive a DSM diagnosis unless other mental health disorders are present (e.g., anxiety, depression).
  5. The DSM guidelines are primarily for psychiatric disorders; therefore, any DSM change will not affect neurologic diagnoses or guidelines. Neurologists tend to predominantly use ICD (WHO) codes, which will only be modified in the psychiatric domain to be aligned with DSM-5.
  6. The RettSearch membership was consulted regarding the DSM changes and the vast majority agreed on them. However, Rett clinicians also realized that it is critical to obtain a unique ICD code for Rett syndrome (currently, generic codes as those for Cerebral Degeneration are mainly used). RettSearch will pursue such a code through a formal application process.
  7. The RettSearch membership thinks that the proposed DSM changes will not affect delivery of services, since any individual with Rett syndrome who needs autism-related services will be able to obtain them through the primary diagnostic label of Autism Spectrum Disorder. RettSearch members also think that a unique ICD code will be greatly beneficial for affected individuals, differentiating them from others with different developmental disorders.

RettSearch Executive Committee Member Honored

We would like to congratulate Dr. John Christodoulou, who was recently appointed a Member of the Order of Australia on January 26, 2010, Australia Day. The award was granted ìfor service to human genetics, particularly the metabolic disorders of children as a researcher and clinician."

Management of Scoliosis in Rett Syndrome Project

To increase awareness of scoliosis in Rett Syndrome, we have written a booklet and a leaflet addressing this important issue. The booklet was published with financial support from the Rett Syndrome Association of Australia and the International Rett Syndrome Foundation. You can also access a pdf of the booklet and leaflet at https://interrett.ichr.uwa.edu.au.

We have published our guidelines in Spine! The published paper is available to members only, and can be found at ./Outcome/files/ Guidelines_Management_Scoliosis_Spine_34_607.pdf

Downs J, Bergman A, Carter P, Anderson A, Palmer GM, Roye D, van Bosse H, Bebbington A, Larsson EL, Smith BG, Baikie G, Fyfe S, Leonard H. Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence. Spine (Phila Pa 1976). 2009 Aug 1;34(17):E607-17.


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