Giuseppe Hayek

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.

MECP2 mutation in male patients with non‐specific X‐linked mental retardation

In contrast to the preponderance of affected males in families with X‐linked mental retardation, Rett syndrome (RTT) is a neurological disorder occurring almost exclusively in females. The near complete absence of affected males in RTT families has been explained by the lethal effect of an X‐linked gene mutation in hemizygous affected males. We report here on a novel mutation (A140V) in the MECP2 gene detected in one female with mild mental retardation. In a family study, the A140V mutation was found to segregate in the affected daughter and in four adult sons with severe mental retardation. These results indicate that MECP2 mutations are not necessarily lethal in males and that they can be causative of non‐specific X‐linked mental retardation.

CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms

Background: Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterised by a wide spectrum of clinical manifestations. Both the classic form and preserved speech variant of Rett syndrome are due to mutations in the MECP2 gene. Several other variants of Rett syndrome have been described. In 1985, Hanefeld described a variant with the early appearance of convulsions. In this variant, the normal perinatal period is soon followed by the appearance of seizures, usually infantile spasms. We have observed two patients with signs of Rett syndrome showing acquired microcephaly and stereotypic midline hand movements. The disease started with generalised convulsions and myoclonic fits at 1.5 months in the first patient and with spasms at 10 days in the other, suggesting a diagnosis of the Hanefeld variant. In these patients, MECP2 point mutations and gross rearrangements were excluded by denaturing high performance liquid chromatography and real time quantitative PCR. The ARX and CDKL5 genes have been associated with West syndrome (infantile spasms, hypsarrhythmia, and mental retardation). Methods: Based on the clinical overlap between the Hanefeld variant and West syndrome, we analysed ARX and CDKL5 in the two girls. Results: We found frameshift deletions in CDKL5 in both patients; one in exon 5 (c.163_166delGAAA) and the other in exon 18 (c.2635_2636delCT). CDKL5 was then analysed in 19 classic Rett and 15 preserved speech variant patients, all MECP2 negative, but no mutations were found. Conclusion: Our results show that CDKL5 is responsible for a rare variant of Rett syndrome characterised by early development of convulsions, usually of the spasm type.

Study of MECP2 gene in Rett syndrome variants and autistic girls.

Mutations in MECP2 gene account for approximately 80% of cases of Rett syndrome (RTT), an X‐linked severe developmental disorder affecting young girls, as well as for most cases of Preserved Speech Variant (PSV), a mild RTT variant in which autistic behavior is common. The aim of this study is to determine whether MECP2 mutations are responsible for PSV only or may cause other forms of autistic disorders. We screened for mutations by SSCP 19 girls with a clinical diagnosis of autism, two of them fulfilling the PSV criteria. A pathogenic mutation was found only in the latter two cases (R133C and R453X). A long follow‐up of these two girls revealed a unique clinical course. They initially developed the first three stages of RTT, they were severely retarded and had autistic behavior. Over the years their abilities increased progressively and by early adolescence they lost autistic behavior, becoming adequately accustomed to people and reaching an IQ close to 45. These results confirm previous clinical studies suggesting that a wide spectrum of RTT exists including girls with mental abilities considerably higher than in classic RTT. We conclude that MECP2 mutations (missense or late truncating) can be found in girls with an IQ close to 45 and a clinical history of PSV of Rett syndrome. Furthermore, MECP2 mutations are not found in patients in which autism remains stable over the years.

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.

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).

Chromosome 2 deletion encompassing the MAP2 gene in a patient with autism and Rett-like features

We present here a unique case of a 14‐year‐old female with autism and some features similar to Rett syndrome (RTT). Genetic analysis demonstrated a large deletion of chromosome 2q instead of a MECP2 mutation. Like a Rett patient, she is dyspraxic and shows frequent hand‐washing stereotypic activities, hyperpnea, and bruxism. Like a preserved speech variant (PSV) of RTT, she is obese, able to speak in second and third persons, frequently echolalic, and has final normal head circumference and autistic behavior. In addition, she has dysmorphic features such as down‐slanting palpebral fissures, low set ears without lobuli, bilateral flat feet, and bilateral syndactyly of the second and third toes, which do not belong to the Rett spectrum. She has a de novo chromosomal deletion in 2q34 of paternal origin. Gene content analysis of the deleted region showed the presence of 47 genes (14 putative and 33 known genes). This region contains some interesting genes such as ADAM23/MDC3, CREB1, KLF7, and MAP2. Because alteration of neuronal maturation, dendritic anomalies, and a decrease in MAP2 immunoreactivity in white matter neurons are well documented in RTT patients, we propose MAP2 gene as a good candidate for the generation of PSV phenotype in this case.

Clinical and molecular characterization of a patient with a 2q31.2-32.3 deletion identified by array-CGH†

We report on a patient with a de novo interstitial deletion of the long arm of chromosome 2 involving bands 2q31.2‐2q32.3. The patient shows severe mental retardation, absence of speech, sleep disturbances, behavioral problems, and some dysmorphic features. In particular, he presents with macrocephaly, high forehead, thick and coarse hair, thick eyebrows, synophrys, increased inner and outer canthal distance, bifid nasal tip, high palate, micrognathia, dysmorphic right ear, and long and tapering fingers. Array‐CGH analysis allowed us to identify and characterize a 2q interstitial deletion of about 13 Mb, involving the segment between cytogenetic bands 2q31.2 and 2q32.3. The deletion was confirmed by quantitative PCR. We compare the phenotype of our patient with those already reported in literature. In particular, we discuss the similarities shared with two recently reported patients, studied by array‐CGH, who show an overlapping deletion. The common clinical features are: long face, high forehead, abnormal teeth and ears, midface hypoplasia, high palate, micrognathia, transparent and thin skin, high frequency of inguinal hernia, severe development impairment, and behavioral problems. Some genes located in the deleted region may be good candidates for the neurological phenotype such as ZNF533 and MYO1B, which are both involved in neuronal function. Furthermore, the GLS gene could be a good candidate in generating the behavioral phenotype in the patient. In fact, it encodes for the major enzyme yielding glutamate from glutamine and it can be implicated in behavioral disturbances in which glutamate acts as a neurotransmitter.

Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation

Duplications leading to functional disomy of chromosome Xq28, including MECP2 as the critical dosage-sensitive gene, are associated with a distinct clinical phenotype in males, characterized by severe mental retardation, infantile hypotonia, progressive neurologic impairment, recurrent infections, bladder dysfunction, and absent speech. Female patients with Xq duplications including MECP2 are rare. Only recently submicroscopic duplications of this region on Xq28 have been recognized in four females, and a triplication in a fifth, all in combination with random X-chromosome inactivation (XCI). Based on this small series, it was concluded that in females with MECP2 duplication and random XCI, the typical symptoms of affected boys are not present. We present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene, both isolated and as the result of a translocation, and compare them with the previously reported cases of small duplications in females. The collected data indicate that the associated phenotype in females is distinct from males with similar duplications, but the clinical effects may be as severe as seen in males.

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.