Reversible autism and intellectual disability in children.

Studies on young children with reversible autism and intellectual disability are discussed. Present evidence suggests a clear cause in a minority of cases including early institutionalization, Landau and Kleffner syndrome, and other early onset epilepsies, intrauterine rubella, and blindness. The majority of cases have normal laboratory results and some have early onset Tourette syndrome. Preliminary data of a follow-up study of this last group are reported in 15 patients suggesting the possibility of two subgroups, one represented by early onset Tourette syndrome phenotype, characterized by a positive family history, and by its appearance at the same time as regression and persistence into adolescence while the other of a different nature. Genetic studies could be of help to clarify this issue and support a diagnosis of favorable outcome in young children.

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.

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. METHOD: We analysed 461 minutes of audio-video recordings containing play situations and the daily routines of six females (aged 7 to 24 months; mean birthweight 3057g, SD 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: From the age of 7 months onwards, we observed two types of vocalizations, 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.

FOXG1 is responsible for the congenital variant of Rett syndrome.

Rett syndrome is a severe neurodevelopmental disease caused by mutations in the X-linked gene encoding for the methyl-CpG-binding protein MeCP2. Here, we report the identification of FOXG1-truncating mutations in two patients affected by the congenital variant of Rett syndrome. FOXG1 encodes a brain-specific transcriptional repressor that is essential for early development of the telencephalon. Molecular analysis revealed that Foxg1 might also share common molecular mechanisms with MeCP2 during neuronal development, exhibiting partially overlapping expression domain in postnatal cortex and neuronal subnuclear localization.

Investigation of modifier genes within copy number variations in Rett syndrome.

MECP2 mutations are responsible for two different phenotypes in females, classical Rett syndrome and the milder Zappella variant (Z-RTT). We investigated whether copy number variants (CNVs) may modulate the phenotype by comparison of array-CGH data from two discordant pairs of sisters and four additional discordant pairs of unrelated girls matched by mutation type. We also searched for potential MeCP2 targets within CNVs by chromatin immunopreceipitation microarray (ChIP-chip) analysis. We did not identify one major common gene/region, suggesting that modifiers may be complex and variable between cases. However, we detected CNVs correlating with disease severity that contain candidate modifiers. CROCC (1p36.13) is a potential MeCP2 target, in which a duplication in a Z-RTT and a deletion in a classic patient were observed. CROCC encodes a structural component of ciliary motility that is required for correct brain development. CFHR1 and CFHR3, on 1q31.3, may be involved in the regulation of complement during synapse elimination, and were found to be deleted in a Z-RTT but duplicated in two classic patients. The duplication of 10q11.22, present in two Z-RTT patients, includes GPRIN2, a regulator of neurite outgrowth and PPYR1, involved in energy homeostasis. Functional analyses are necessary to confirm candidates and to define targets for future therapies.

Rett syndrome: revised diagnostic criteria and nomenclature.

OBJECTIVE: Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was to revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials. METHOD: RettSearch members, representing the majority of the international clinical RTT specialists, participated in an iterative process to come to a consensus on a revised and simplified clinical diagnostic criteria for RTT. RESULTS: The clinical criteria required for the diagnosis of classic and atypical RTT were clarified and simplified. Guidelines for the diagnosis and molecular evaluation of specific variant forms of RTT were developed. INTERPRETATION: These revised criteria provide clarity regarding the key features required for the diagnosis of RTT and reinforce the concept that RTT is a clinical diagnosis based on distinct clinical criteria, independent of molecular findings. We recommend that these criteria and guidelines be utilized in any proposed clinical research.

CDKL5 mutations may mimic Pitt-Hopkins syndrome phenotype.

Genetic conditions comprise a wide spectrum of different phenotypes, rapidly expanding due to new diagnostic methodologies. Patients' facial features and clinical history represent the key elements leading clinicians to the right diagnosis. CDKL5-early onset epilepsy and Pitt-Hopkins syndrome are two well-known genetic conditions, with a defined phenotype sharing some common characteristics like early-onset epilepsy and hyperventilation episodes. Whilst facial features represent a diagnostic handle in patients with Pitt-Hopkins syndrome, clinical history is crucial in patients carrying a mutation in CDKL5. Here we present the clinical case of a girl evaluated for the first time when she was 24-years old, with a clinical phenotype mimicking Pitt-Hopkins syndrome. Her facial features have become coarser while she was growing up, leading geneticists to raise different clinical hypotheses and to perform several molecular tests before getting the diagnosis of CDKL5-early-epileptic encephalopathy. This finding highlights that although typical facial gestalt has not so far extensively been described in CDKL5 mutated adult patients, peculiar facial features could be present later in life and may let CDKL5-related disorder mimic Pitt Hopkins. Thus, considering atypical Rett syndrome in the differential diagnosis of Pitt Hopkins syndrome could be important to solve complex clinical cases.

Sympathetic overactivity and plasma leptin levels in Rett syndrome.

Rett syndrome (RTT) is a severe developmental-neurological disorder, characterized by profound and progressive loss of intellectual functioning, occurring after a period (of at least 6 months) of normal development with classic stereotype hand movements, gait ataxia, jerky truncal ataxia, deceleration of brain and body organ growth and cardiac dysautonomia. Pathogenesis of sympathetic overactivity in RTT is unknown, but a previous study observed increased plasma leptin levels in Rett girls and it is well known the role of leptin in the regulation of sympathetic nervous system activity. Aim of our study is to evaluate a relationship between plasma leptin levels and sympathetic activity in RTT. Thirty-two female patients (12.1+/-6.3 years), affected by RTT were enrolled in the study. In all the subjects, we analyzed heart rate variability, QT corrected interval and plasma leptin levels. A significant correlation was found between plasma leptin levels and LF/HF (expression of sympatho-vagal balance) (Spearman r=0.44, p=0.001). There is also a significant negative correlation between HF component (expression of vagal activity) and plasma leptin levels (Spearman r=-0.037, p=0.03) and a positive correlation between LF component and plasma leptin levels (Spearman r=0.047, p=0.01). These results show that in RTT higher plasma leptin levels appear to be associated with sympathetic overactivity, suggesting a role for leptin in cardiac dysautonomia.

Polydactyly with ectodermal defect, osteopenia, and mental delay.

Five members from 3 generations, including a 35-year-old woman and her 2 sons, both mentally impaired to a different degree, were studied in a tertiary care hospital. Anamnestic, clinical, neurological, and radiological evaluations were used to describe phenotypes. A and B postaxial polydactyly, transmitted likely as autosomal dominant, was associated with an extensive variability of phenotypic features: (1) cutaneous syndactyly, (2) nail-teeth dysplasia, (3) osteopenia, and (4) mental delay. The likelihood that the constellation of observations we report here is caused by mutation of a single gene that subsequently affects multiple physiological activities, although fascinating, remains to be proven. Instead, we hypothesize that it likely develops as a contiguous gene syndrome.

Italian Rett database and biobank.

Rett syndrome is the second most common cause of severe mental retardation in females, with an incidence of approximately 1 out of 10,000 live female births. In addition to the classic form, a number of Rett variants have been described. MECP2 gene mutations are responsible for about 90% of classic cases and for a lower percentage of variant cases. Recently, CDKL5 mutations have been identified in the early onset seizures variant and other atypical Rett patients. While the high percentage of MECP2 mutations in classic patients supports the hypothesis of a single disease gene, the low frequency of mutated variant cases suggests genetic heterogeneity. Since 1998, we have performed clinical evaluation and molecular analysis of a large number of Italian Rett patients. The Italian Rett Syndrome (RTT) database has been developed to share data and samples of our RTT collection with the scientific community (http://www.biobank.unisi.it). This is the first RTT database that has been connected with a biobank. It allows the user to immediately visualize the list of available RTT samples and, using the "Search by" tool, to rapidly select those with specific clinical and molecular features. By contacting bank curators, users can request the samples of interest for their studies. This database encourages collaboration projects with clinicians and researchers from around the world and provides important resources that will help to better define the pathogenic mechanisms underlying Rett syndrome.

MECP2 deletions and genotype-phenotype correlation in Rett syndrome.

Rett syndrome is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. MECP2 point mutations in exons 2-4 account for about 80% of classic Rett cases and for a lower percentage of variant patients. We investigated the genetic cause in 77 mutation-negative Rett patients (33 classic, 31 variant, and 13 Rett-like cases) by searching missed MECP2 defects. DHPLC analysis of exon 1 and MLPA analysis allowed us to identify the defect in 17 Rett patients: one exon 1 point mutation (c.47_57del) in a classic case and 16 MECP2 large deletions (15/33 classic and 1/31 variant cases). One identical intragenic MECP2 deletion, probably due to gonadal mosaicism, was found in two sisters with discordant phenotype: one classic and one "highly functioning" preserved speech variant. This result indicates that other epigenetic or genetic factors, beside MECP2, may contribute to phenotype modulation. Three out of 16 MECP2 deletions extend to the adjacent centromeric IRAK1 gene. A putative involvement of the hemizygosity of this gene in the ossification process is discussed. Finally, results reported here clearly indicate that MECP2 large deletions are a common cause of classic Rett, and MLPA analysis is mandatory in MECP2-negative patients, especially in those more severely affected (P = 0.044).

Kabuki syndrome with trichrome vitiligo, ectodermal defect and hypogammaglobulinemia A and G.

We report a unique combination of symptoms in a case of Kabuki syndrome (KS), a multiple malformation/mental retardation syndrome that has a prevalence of 1:32,000 to 1:86,000. The patient was a mentally delayed 12-year-old male with trichrome vitiligo, ectodermal defect, and hypogammaglobulinemia A and G. This unique combination of signs, described here for the first time, indicates that KS comprises multiple deficits that affect not only the brain, but ectoderm-derived structures and the immune system as well. Our report may provide important clues for understanding the pathogenesis of the KS.

Myoclonic encephalopathy in the CDKL5 gene mutation.

OBJECTIVE: Epilepsy with mutation of the CDKL5 gene causes early seizures and is a variant of Rett syndrome (MIM (312750), which is reported typically as infantile spasms. The purpose of this study was to analyze the epileptic histories and EEGs of patients with the CDKL5 mutation. METHODS: We reviewed the epilepsy histories and electroclinical analyses of three girls aged 9.5, 7.4, and 9.4 years, each with a mutation of the CDKL5 gene. RESULTS: We revealed the presence of an encephalopathy that started by 1.5 months of age. At first, seizures involved tonic spasms or complex partial seizures, and were complicated by the later appearance of complex partial, tonic, and unexpectedly, myoclonic seizures. This form of epilepsy was drug resistant. Routine and prolonged video EEGs both displayed a homogeneous electroclinical pattern consisting of (a) unique background with diffuse high voltage sharp waves of 6-7 Hz, and absence of the typical rhythmic frontal-central theta activity present in Rett syndrome; (b) unique awake and sleep background, with diffuse, high voltage, continuous sharp waves with multifocal and diffuse spikes; (c) rhythmic, diffuse, 15 Hz activity accompanied clinically by tonic seizures; (d) intercritical pattern with pseudoperiodic, diffuse, sharp waves or pseudoperiodic, diffuse spike and polyspike or wave discharges; and (e) diffuse, spike, polyspike and wave discharges accompanied by massive or focal myoclonias or both. CONCLUSIONS: Patients with the CDKL5 mutation have an early onset, epileptic encephalopathy in infancy that evolves into myoclonic seizures in childhood with a unique EEG pattern. SIGNIFICANCE: Recognizing this type of encephalopathy could be useful in prompting clinicians to proceed further with their diagnostic work in patients not fitting the criteria of classical Rett syndrome.

Global developmental delay, osteopenia and ectodermal defect: a new syndrome.

UNLABELLED: Global developmental delay is a serious social problem. It is often unrecognized and the phenotypes are inadequately studied. To investigate the phenotypes of children with aspecific central nervous system (CNS) impairment (poor speech, maladaptive behavioral symptoms such as temper tantrums, aggressiveness, poor concentration and attention, impulsiveness, and mental retardation). SETTING: Tertiary care hospital. PATIENTS: Three children (two male siblings, and one unrelated girl). METHODS: We used the results from clinical neurological evaluations; imaging and electrodiagnostic studies; metabolic and genetic tests; skin biopsies and bone mineral densitometry. All three children suffered from (A) global developmental delay, (B) osteopenia, and (C) identical skin defects. The skin ultrastructural abnormalities were abnormal keratin differentiation, consisting of hyperkeratosis and granular layer thickening; sweat gland abnormalities, consisting of focal, cytoplasmic clear changes in eccrine secretory cells; and melanocyte abnormalities, with both morphological changes (reduced number and size without evident dendritic processes), and functional changes (defects in the migration of melanosomes in the keratinocytes). These patients present a previously unrecognized syndrome. We retain useful to report this new association, to be recognized, in the next future, as a specific key-sign of a well-defined genetic defect.

Autistic epileptiform regression.

Autistic regression is a well known condition that occurs in one third of children with pervasive developmental disorders, who, after normal development in the first year of life, undergo a global regression during the second year that encompasses language, social skills and play. In a portion of these subjects, epileptiform abnormalities are present with or without seizures, resembling, in some respects, other epileptiform regressions of language and behaviour such as Landau-Kleffner syndrome. In these cases, for a more accurate definition of the clinical entity, the term autistic epileptifom regression has been suggested. As in other epileptic syndromes with regression, the relationships between EEG abnormalities, language and behaviour, in autism, are still unclear. We describe two cases of autistic epileptiform regression selected from a larger group of children with autistic spectrum disorders, with the aim of discussing the clinical features of the condition, the therapeutic approach and the outcome.

Epilepsy, electroencephalographic abnormalities, and regression in children with autism.

The association of epilepsy and autism is recognized, and it has been reported at a percentage that varies between 8 and 42%, depending on age and diagnostic criteria. One third of autistic children undergo a regression of language and behavior between 2 and 3 years, and epileptiform abnormalities and epilepsy can be concomitant in an undetermined percentage of them. The aim of this study was to investigate the prevalence of epilepsy and paroxysmal abnormalities in a group of children with autism and to determine the percentage of regression course in this group. Forty-six patients with autism (mean age 7.8 +/- 2.7 years; 34 boys and 12 girls) were consecutively examined, and clinical evaluation, assessment, and electroencephalographic (EEG) recordings were performed in all of them. Thirty-five percent showed paroxysmal abnormalities and epilepsy, 22% had only paroxysmal abnormalities without seizures, and 13% of the children suffered from epilepsy. Sixty-five percent had a normal EEG. No difference in regression rate was observed between patients with paroxysmal abnormalities and epilepsy and those with a normal EEG and without seizures. In the study group, the prevalence of epilepsy was in the low range of individuals with autism, and different types of epilepsy were observed. Autism with regression was not influenced by paroxysmal abnormalities and epilepsy.

What do home videos tell us about early motor and socio-communicative behaviours in children with autistic features during the second year of life--An exploratory study.

BACKGROUND: Little is known about the first half year of life of individuals later diagnosed with autism spectrum disorders (ASD). There is even a complete lack of observations on the first 6 months of life of individuals with transient autistic behaviours who improved in their socio-communicative functions in the pre-school age. AIM: To compare early development of individuals with transient autistic behaviours and those later diagnosed with ASD. STUDY DESIGN: Exploratory study; retrospective home video analysis. SUBJECTS: 18 males, videoed between birth and the age of 6 months (ten individuals later diagnosed with ASD; eight individuals who lost their autistic behaviours after the age of 3 and achieved age-adequate communicative abilities, albeit often accompanied by tics and attention deficit). METHOD: The detailed video analysis focused on general movements (GMs), the concurrent motor repertoire, eye contact, responsive smiling, and pre-speech vocalisations. RESULTS: Abnormal GMs were observed more frequently in infants later diagnosed with ASD, whereas all but one infant with transient autistic behaviours had normal GMs (p<0.05). Eye contact and responsive smiling were inconspicuous for all individuals. Cooing was not observable in six individuals across both groups. CONCLUSIONS: GMs might be one of the markers which could assist the earlier identification of ASD. We recommend implementing the GM assessment in prospective studies on ASD.

Real-time quantitative PCR as a routine method for screening large rearrangements in Rett syndrome: Report of one case of MECP2 deletion and one case of MECP2 duplication.

Mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) are found in 70-80% of cases of classical Rett syndrome (RTT) and in about 50% of cases of preserved speech variant (PSV). This high percentage of MECP2 mutations, especially in classical RTT cases, suggests that another major RTT locus is unlikely. Missed mutations may be due to the limited sensitivity of the methodology used for mutation scanning and/or the presence of intronic mutations. In a double-copy gene, such as MECP2 in females, current methodologies (e.g., DGGE, SSCP, DHPLC, direct sequencing) are prone to miss gross rearrangements. Three previous reports during 2001-2003 have shown the presence of large deletions in a fraction of MECP2-negative classical RTT patients. We developed a reliable, single tube, quantitative PCR assay for rapid determination of MECP2 gene dosage. This method involves a multiplex reaction using a FAM labeled TaqMan probe with a TAMRA quencher derived from MECP2 exon 4 and two primers derived from the same exon and RNAaseP as an internal reference. The copy number of the MECP2 gene was determined by the comparative threshold cycle method (ddCt). Each sample was run in quadruplicate. We validated this assay through the analysis of 30 healthy controls (15 female and 15 male) and we then applied this method to eight classical RTT and six PSV patients, all negative for MECP2 mutations. We identified gross rearrangements in two patients: a deletion in a classical RTT patient and a duplication in a PSV patient. Our results confirm that a fraction of MECP2-negative RTT cases have MECP2 gross rearrangements and we propose real-time quantitative PCR as a simple and reliable method for routine screening of MECP2 in addition to DHPLC analysis.

Three Rett patients with both MECP2 mutation and 15q11-13 rearrangements.

Autism and Rett syndrome, a severe neurological disorder with autistic behavior, are classified as separate disorders on clinical and etiological ground. Rett syndrome is a monogenic X-linked dominant condition due to de novo mutations in the MECP2 gene, whereas autism is a neurodevelopmental and behavioral disorder with complex genetic basis. Maternally inherited duplications on 15q11-q13 are found in a fraction of autistic children suggesting that an abnormal dosage of gene(s) within this region might cause susceptibility to autism. Now we show that three Rett patients are carriers of both a MECP2 mutation and a 15q11-q13 rearrangement, suggesting that there might be a relationship between autism-related genes and the MECP2 gene.

Analysis of ten candidate genes in autism by association and linkage.

We studied the possible involvement of ten candidate genes in autism: proenkephalin, prodynorphin, and proprotein convertase subtilisin/kexin type 2 (opioid metabolism); tyrosine hydroxylase, dopamine receptors D2 and D5, monoamine oxidases A and B (monoaminergic system); brain-derived neurotrophic factor, and neural cell adhesion molecule (involved in neurodevelopment). Thirty-eight families with two affected siblings and one family with two affected half-siblings, recruited by the Paris Autism Research International Sibpair Study (PARIS), were tested using the transmission disequilibrium test and two-point affected sib-pair linkage analysis. We found no evidence for association or linkage with intragenic or linked markers. Our family sample has good power for detecting a linkage disequilibrium of 0.80. Thus, these genes are unlikely to play a major role in the families studied, but further studies in a much larger sample would be needed to highlight weaker genetic effects.