Autism spectrum disorders are not rare; many primary care pediatricians care for several children with autism spectrum disorders. Pediatricians play an important role in early recognition of autism spectrum disorders, because they usually are the first point of contact for parents. Parents are now much more aware of the early signs of autism spectrum disorders because of frequent coverage in the media; if their child demonstrates any of the published signs, they will most likely raise their concerns to their child's pediatrician. It is important that pediatricians be able to recognize the signs and symptoms of autism spectrum disorders and have a strategy for assessing them systematically. Pediatricians also must be aware of local resources that can assist in making a definitive diagnosis of, and in managing, autism spectrum disorders. The pediatrician must be familiar with developmental, educational, and community resources as well as medical subspecialty clinics. This clinical report is 1 of 2 documents that replace the original American Academy of Pediatrics policy statement and technical report published in 2001. This report addresses background information, including definition, history, epidemiology, diagnostic criteria, early signs, neuropathologic aspects, and etiologic possibilities in autism spectrum disorders. In addition, this report provides an algorithm to help the pediatrician develop a strategy for early identification of children with autism spectrum disorders. The accompanying clinical report addresses the management of children with autism spectrum disorders and follows this report on page 1162 [available at www.pediatrics.org/cgi/content/full/120/5/1162]. Both clinical reports are complemented by the toolkit titled "Autism: Caring for Children With Autism Spectrum Disorders: A Resource Toolkit for Clinicians," which contains screening and surveillance tools, practical forms, tables, and parent handouts to assist the pediatrician in the identification, evaluation, and management of autism spectrum disorders in children.

/pdf/identification-and-evaluation-of-children-with-autism-47d21l77u4.pdf

Identification and Evaluation of Children With Autism Spectrum Disorders

Rett syndrome, one of the leading causes of mental retardation and developmental regression in girls, is the first pervasive developmental disorder with a known genetic cause. The majority of cases of sporadic Rett syndrome are caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). MeCP2 binds methylated DNA and likely regulates gene expression and chromatin structure. Genotype/phenotype analysis revealed that the phenotypic spectrum of MECP2 mutations in humans is broader than initially suspected: Mutations have been discovered in Rett syndrome variants, mentally retarded males, and autistic children. A variety of in vivo and in vitro models has been developed that allow analysis of MeCP2 function and pathogenic studies of Rett syndrome. Because the neuropathology of Rett syndrome shares certain features with other neurodevelopmental disorders, a common pathogenic process may underlie these disorders. Thus, Rett syndrome is a prototype for the genetic, molecular, and neurobiologic...

Rett Syndrome: A Prototypical Neurodevelopmental Disorder

The orchestrated organization of epigenetic factors that control chromatin dynamism, including DNA methylation, histone marks, non-coding RNAs (ncRNAs) and chromatin-remodeling proteins, is essential for the proper function of tissue homeostasis, cell identity and development. Indeed, deregulation of epigenetic profiles has been described in several human pathologies, including complex diseases (such as cancer, cardiovascular and neurological diseases), metabolic pathologies (type 2 diabetes and obesity) and imprinting disorders. Over the last decade it has become increasingly clear that mutations of genes involved in epigenetic mechanism, such as DNA methyltransferases, methyl-binding domain proteins, histone deacetylases, histone methylases and members of the SWI/SNF family of chromatin remodelers are linked to human disorders, including Immunodeficiency Centromeric instability Facial syndrome 1, Rett syndrome, Rubinstein–Taybi syndrome, Sotos syndrome or alpha-thalassemia/mental retardation X-linked syndrome, among others. As new members of the epigenetic machinery are described, the number of human syndromes associated with epigenetic alterations increases. As recent examples, mutations of histone demethylases and members of the non-coding RNA machinery have recently been associated with Kabuki syndrome, Claes-Jensen X-linked mental retardation syndrome and Goiter syndrome. In this review, we describe the variety of germline mutations of epigenetic modifiers that are known to be associated with human disorders, and discuss the therapeutic potential of epigenetic drugs as palliative care strategies in the treatment of such disorders.

https://static.springer.com/sgw/documents/1390418/application/pdf/HG1.pdf

Genetic syndromes caused by mutations in epigenetic genes

Introduction: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that is usually associated with mutations in the MECP2 gene. The most common mutations in the gene are p.R168X and p.T158M. The influence of X-chromosome inactivation (XCI) on clinical severity in patients with RTT with these mutations was investigated, taking into account the extent and direction of skewing.

Methods: Female patients and their parents were recruited from the UK and Australia. Clinical severity was measured by the Pineda Severity and Kerr profile scores. The degree of XCI and its direction relative to the X chromosome parent of origin were measured in DNA prepared from peripheral blood leucocytes, and allele-specific polymerase chain reaction was used to determine the parental origin of mutation. Combining these, the percentage of cells expected to express the mutant allele was calculated.

Results: Linear regression analysis was undertaken for fully informative cases with p.R168X (n = 23) and p.T158M (n = 20) mutations. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both the p.R168X and p.T158M mutations.

Conclusions: XCI may vary in neurological and haematological tissues. However, these data are the first to show a relationship between the degree and direction of XCI in leucocytes and clinical severity in RTT, although the clinical utility of this in giving a prognosis for individual patients is unclear.

https://jmg.bmj.com/content/jmedgenet/44/2/148.full.pdf

Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation

MECP2 mutations mainly occur in females with Rett syndrome. Mutations have been described in 11 boys with progressive encephalopathy: seven of nine with affected sisters and two de novo. The authors report four de novo occurrences: three pathogenic and one potentially pathogenic. Common features include failure to thrive, respiratory insufficiency, microcephaly, and abnormal motor control. MECP2 mutations should be assessed in boys with progressive encephalopathy and one or more of respiratory insufficiency, abnormal movements or tone, and intractable seizures.

Early progressive encephalopathy in boys and MECP2 mutations.

Rett syndrome (RS, MIM 312750) is an X linked dominant neurodevelopmental disorder, which has been considered to affect girls only.1 Males were thought to be aborted spontaneously or to have a different phenotype.2

The disease is caused by mutations in MECP2 , encoding a methyl-CpG binding protein MeCP2.3 MeCP2 is an abundantly expressed protein acting as a global transcription repressor.4 The protein contains two domains, the 85 amino acid methyl-CpG binding domain (MBD) and the 102 amino acid transcriptional repression domain (TRD).4,5 Furthermore, a domain in the C terminal part of the protein, facilitating DNA binding and harbouring the nuclear localising signal (NLS), has been described.6

The mutation responsible for RS has now been found in the majority of RS patients and more than 100 different mutations have been published. Although some association between phenotype and genotype has been shown, their correlation is not predictive of the clinical manifestations in the individual case.7,8

Since 1999, when mutations in MECP2 were first reported in patients with RS,3 it has been possible to analyse boys for mutations resulting in a confirmation of the diagnosis in some of the earlier reported cases.9,10

Screening of groups of patients with mental retardation of different types has further identified MECP2 mutations in males. So far, 17 cases of males with a disease causing mutation in MECP2 have been found. However, six of them were found to have Klinefelter syndrome or were mosaics for the mutation in question.8–15 The latter can roughly be divided into two groups, the severe neonatal cases, who die within the first years of life, all caused by an MECP2 mutation that in females causes classical RS,8–10 and the non-specific mental retardation type with mutations that, if …

https://jmg.bmj.com/content/jmedgenet/40/1/e5.full.pdf

No correlation between phenotype and genotype in boys with a truncating MECP2 mutation

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No correlation between phenotype and genotype in boys with a truncating MECP2 mutation