Classic Rett syndrome in a boy with R133C mutation of MECP2

doi:10.1016/j.braindev.2004.10.002

Brain and Development

Volume 27, Issue 6, September 2005, Pages 439-442

https://doi.org/10.1016/j.braindev.2004.10.002 Get rights and content

Abstract

About 80% of female patients with Rett syndrome (RTT) display a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, but most males with MECP2 mutation experience severe fatal encephalopathy or non-specific X-linked mental retardation (XLMR). The existence of male RTT has been extensively discussed. We report herein a boy with classic RTT in a family with a missense mutation in MECP2. The mother exhibited slight mental retardation and was a carrier for R133C. The patient could stand with support at 12-months-old, and stereotypic hand movements appeared at 3-years-old. He became bed-ridden by 8-years-old. The R133C mutation was present in MECP2 without somatic mosaicism. A sister with R133C displayed classic RTT. The R133C mutation has been detected in female patients with classic and preserved speech variant RTT, but not in males with non-specific XLMR. These results suggest that clinical phenotypes caused by DNA mutation in MECP2 are determined by position of the mutation in the gene, and R133 represents a critical amino acid residue in the induction of RTT symptoms in humans.

Introduction

Rett syndrome (RTT, OMIM 312750) is a developmental disorder occurring primarily in girls, with symptoms such as autistic tendencies, severe mental deficiency and characteristic stereotypic hand movements appearing with age [1]. Most cases are sporadic, but a few familial cases of RTT have been reported [2]. In families with an RTT daughter, however, affected sons have displayed severe encephalopathy resulting in early postnatal death [2]. The existence of classic RTT in males has thus been extensively discussed [3].

Since the gene encoding methyl CpG-binding protein 2 (MECP2) was mapped to Xq28 and identified as the culprit gene for RTT [4], a wide range of MECP2 mutations have been detected in female RTT patients [5]. As expected, males displaying MECP2 mutations have exhibited severe encephalopathy in these RTT families [6]. MECP2 mutations with somatic mosaicism [7], [8] or an additional X chromosome, resulting in a 47, XXY karyotype [9], have subsequently been identified in male patients with classic RTT. In addition, MECP2 mutations have been reported in males with the X-linked non-specific mental retardation (XLMR) syndrome [10], [11]. Whether classic RTT exists in males with a pure male karyotype remains obscure.

We report herein the case of a boy with classic RTT who was hemizygous for MECP2 mutation. This family provides very interesting information regarding the relationship between clinical symptoms associated with RTT and the location of MECP2 mutations, and the role of skewed X chromosome inactivation.

Section snippets

Case report

The patient was the second child of unrelated parents who both displayed very mild intellectual impairment, but who have led independent lives. No abnormalities were noted throughout gestation and the patient was delivered at 38 weeks of gestation with a birth weight of 2528 g, height of 49 cm, and head circumference of 31.5 cm. Developmental delays were confirmed after he started to smile from 3-months-old, Head control was achieved at 6-months-old and rolling at 7-months-old. Hypotonia was

Methods

MECP2 mutation was detected as follows. Genomic DNA was extracted from peripheral blood leukocytes using standard protocols. DNA amplification of MECP2 coding exons by polymerase chain reaction (PCR) was performed using appropriate primer pairs and conditions, as reported previously [12]. PCR products were then sequenced directly using an ABI 1310 sequencer (Applied Biosystems Japan, Tokyo).

The X inactivation pattern was determined by PCR analysis of a polymorphic CAG repeat in the androgen

Results

The C-to-T change at 397 in exon 4 of MECP2 that resulted in R133C was detected in three members of this family (Fig. 2(A)). The mother and the sister were heterozygous for R133C (Fig. 2(A): M and S), and the boy had only one allele, C133, derived from the mother (Fig. 2(A): P). The father displayed a wild-type allele, Rl33 (Fig. 2(A): F). The boy had a normal 46, XY karyotype and no PCR product from wild-type MECP2 was detected, suggesting that somatic mosaicism can be excluded as a

Discussion

MECP2 is a silencing gene that controls timing for the inactivation of numerous functional genes in the perinatal period. MECP2 abnormalities can therefore result in expression of genes at inappropriate times and inhibition of normal growth. Various mutations, including nonsense, missense, and frame-shift mutations have been documented [5]. Mutations associated with RTT are predominantly localized at the two functional domains of the MeCP2 protein—the methyl-binding domain (MBD) and the

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MECP2-related conditions in males: A systematic literature review and 8 additional cases
2021, European Journal of Paediatric Neurology
Citation Excerpt :
Our clinical findings overlapped with the 27 reported individuals with severe neonatal encephalopathy and similar outcomes. Molecular analysis disclosed three missense pathogenic variants: two variants [p.(Arg133His) and p.(Arg133Cys)] previously reported in males with severe neonatal encephalopathy [17,26,28] and also described in several cases of female patients with classical RS [29]; and the missense variant p.(Arg306Cys), not previously reported in males, but seen many times in female patients with classical RS [29]. Two frameshift pathogenic variants were identified: p.(Gly269Alafs∗20), previously reported in 3 males with epileptic encephalopathy [16,18,24] and p.(Gly252Argfs∗7), which is a novel variant.
To present a cohort of 8 males and perform a systematic review of all published cases with a single copy of MECP2 carrying a pathogenic variant.
We reviewed medical records of males with a single copy of MECP2 carrying a pathogenic variant. We searched in Medline (Pubmed) and Embase to collect all articles which included well-characterized males with a single copy of MECP2 carrying a pathogenic or likely pathogenic variant in MECP2 (1999–2020).
The literature search yielded a total of 3,185 publications, of which 58 were included in our systematic review. We were able to collect information on 27 published patients with severe neonatal encephalopathy, 47 individuals with isolated or familial mental retardation X-linked 13 (XLMR13), as well as 24 individuals with isolated or familial Pyramidal signs, parkinsonism, and macroorchidism (PPM-X).
In our cohort, we met eight individuals aged 4 to 19-year-old at the last evaluation. Three MECP2-associated phenotypes were seen in male carriers of a single copy of the gene: severe neonatal encephalopathy (n = 5); X-linked intellectual deficiency 13 (n = 2); and pyramidal signs, parkinsonism, and macroorchidism (PPM-X) (n = 1). Two novel de novo variants [p.(Gly252Argfs∗7) and p.(Tyr132Cys)] were detected.
In males, the MECP2 pathogenic variants can be associated with different phenotypes, including neonatal severe encephalopathy, intellectual deficiency, or late-onset parkinsonism and spasticity. The typical RS phenotype is not expected in males, except in those with Klinefelter syndrome or somatic mosaicism for MECP2.
Induced pluripotent stem cells for modeling of Rett Syndrome
2021, iPSCs for Modeling Central Nervous System Disorders, Volume 6
Rett Syndrome (RTT) is an X-linked dominant neurodevelopmental disorder which specifically affecting females. Majority of the cases of RTT is caused because of mutation in methyl-CpG-binding protein (MECP2) gene; besides few cases are caused because of mutation in CDKL5 and FOXG1 gene as well. Since the RTT is a severe disorder and MECP2 and CDKL5 are X linked disorder, therefore, only females are affected. Since, males are hemizygous for X chromosome, therefore, males could not survive with these mutations. In contrast, RTT in males is because of mutations in FOXG1 gene, an autosomal gene. Microcephaly is the prominent phenotype among Rett patients characterized by progressive loss of intellectual functioning, development of stereotypic hand movement, seizures etc.
To study the disease pathogenesis, live patients’ neurons are the best suited model system, however, getting patients live brain cells are impossible from an affected individual and also ethically not permissible. Therefore, development of a model system to recapitulate the phenotype of the syndrome with same genome as that of patient is essential. This can be done by using induced pluripotent stem cells (iPSCs) techniques. The main advantage of iPSCs is that it can be used to generate any type of brain cells, even a miniature brain organoid called cerebral organoid can also be generated which can be used to study cross talk between genes and their effects on different brain tissues.
The first iPSCs model for Rett was developed by Ellis group in 2009. Subsequently, various researchers successfully generated Rett-iPSCs to evaluate different mutations pertaining to Rett phenotypes. The neurons differentiated from patient-specific iPSCs exhibits similar phenotypes as that of the patients, like reduced soma and nuclear size, decreased dendritic spine density, fewer synapse, altered calcium signaling, etc. It was demonstrated through iPSCs that there is overexpression of GABAergic gene products with MECP2 mutant iPSC-derived neurons while reduced functional synaptic contact and impaired neuronal activity were demonstrated in CDKL5 mutant iPSCs-derived neurons. Moreover, iPSCs-derived neurons from FOXG1-mutated patients showed increased level of GRID1 mRNA levels that regulate synaptic differentiation and thus have altered effect on normal development.
Besides the disease pathogenesis study, efforts are also on for cellular therapy as well as evaluating different drug candidates. With the help of latest gene editing technique CRISPR/Cas9, various groups are trying to restore the functionality of MECP2 gene which can lead to a promising way toward treatment for Rett. This technique of iPSCs will be helpful not only for studying RTT in depth but also can pave a path toward drug development to ease the quality of life of the affected children.
Breathing disturbances in a model of Rett syndrome: A potential involvement of the glycine receptor α3 subunit?
2018, Respiratory Physiology and Neurobiology
The glycine receptor α3 subunit is known to be a target for cAMP/PKA-mediated phosphorylation and regulation. Mice that lack this subunit are apparently normal but the 5-HT_1A-receptor mediated modulation of respiratory network activity is disturbed. Since the intracellular cAMP-concentration is reduced in mice that lack the transcriptional modulator methyl-CpG-binding protein 2 (MeCP2) gene, we aimed to test if the α3 subunit of the glycine receptor is involved in the development of the breathing phenotype of MeCP2-deficient mice (Mecp2^−/y). Therefore, we generated a double knock-out mouse line that lacks both the Mecp2 gene as well as the gene (Glra3) for the α3 subunit of the ionotropic glycine receptor. As compared to WT and Glra3^−/− mice, both Mecp2^−/y mice and Mecp2^−/y; Glra3^−/− mice (DKO) showed a slower respiratory rate and a tendency towards higher numbers of apneas. Interestingly, the irregularity of the breathing was significantly reduced in DKO as compared to Mecp2^−/y littermates. In the light of the unaltered survival of DKO mice, however, the contribution of the glycine receptor α3 subunit for development and progression of the breathing disturbances in the mouse model of Rett syndrome appears to be only of minor relevance.
Males With MECP2 C-terminal-Related Atypical Rett Syndromes and Their Carrier Mothers
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Citation Excerpt :
Male phenotypes of these gene mutations range from lethal congenital and neonatal encephalopathies2 to PPM-X syndrome (psychosis and parkinsonism),5 nonspecific intellectual impairment,6 and other atypical presentations with ill-defined regression.7 Only a minority of males resemble the classic female RTT.8-10 Recognition and classification of male syndrome(s) continue to challenge clinicians and researchers.
This communication examines the expanding phenotypes of the MECP2 C-terminal atypical Rett syndromes in males and their affected carrier mothers.
We describe three males with normal karyotypes who presented with congenital evolving complex neurodevelopmental encephalopathies with multifaceted symptomatology of hypotonia, epilepsy, ataxia, spasticity, movement disorders, behavioral issues, severe intellectual impairment, and communication skills, and a protracted regression phase followed by stabilization. These phenotypes did not prompt us to identify atypical Rett syndrome early in childhood.
Genetic analysis identified the two brothers with C-terminal truncation and the third male with C-terminal missense mutations. These mutations were inherited from their mothers, both of whom had incompletely characterized modest intellectual, mental health, social, and gastrointestinal impairments. Neither was independently able to care properly for their son(s).
Mutations of the MECP2 gene should be considered early in males with hypotonia, developmental delay, profound intellectual impairment, and seizures, associated with a mother with psychosocial, cognitive, and gastrointestinal impairments. Counseling and supporting mildly affected mothers requires both medical and social efforts.
Mouse models of neurodevelopmental disease of the basal ganglia and associated circuits
2014, Current Topics in Developmental Biology
Citation Excerpt :
Autism, ataxia, and seizures (Dolce, Ben-Zeev, Naidu, & Kossoff, 2013) are also characteristic following developmental regression, with Parkinsonism and dystonia occurring in older patients (FitzGerald, Jankovic, Glaze, Schultz, & Percy, 1990). While RTT occurs almost exclusively in females, in boys, MECP2 mutations can cause neonatal lethality (Villard et al., 2000) or, on rare occasion, an RTT-like phenotype (Armstrong, Pineda, Aibar, Gean, & Monros, 2001; Dayer et al., 2007; Masuyama et al., 2005), likely due to somatic mosaicism (Armstrong et al., 2001). On purely clinical grounds, the highly stereotyped hand movements that occur in RTT are reminiscent of tic/compulsive-like behavior, and similar to the stereotypies that result from striatal dysfunction in experimental animals (Berridge et al., 2005; Welch et al., 2007).
This chapter focuses on neurodevelopmental diseases that are tightly linked to abnormal function of the striatum and connected structures. We begin with an overview of three representative diseases in which striatal dysfunction plays a key role—Tourette syndrome and obsessive-compulsive disorder, Rett's syndrome, and primary dystonia. These diseases highlight distinct etiologies that disrupt striatal integrity and function during development, and showcase the varied clinical manifestations of striatal dysfunction. We then review striatal organization and function, including evidence for striatal roles in online motor control/action selection, reinforcement learning, habit formation, and action sequencing. A key barrier to progress has been the relative lack of animal models of these diseases, though recently there has been considerable progress. We review these efforts, including their relative merits providing insight into disease pathogenesis, disease symptomatology, and basal ganglia function.
Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations
2009, Neurobiology of Disease
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RTT affects approximately 1:10,000 females worldwide, and prominent symptoms include deceleration of body and head growth rate, hand stereotypies and regression in motor and speech capabilities, irregularities in motor activity and breathing patterns, in addition to cognitive impairments characteristic of an autism-spectrum disorder (reviewed by Percy and Lane, 2005). Although RTT occurs predominantly in females, mutations of MECP2 have also been identified in males, where the phenotypes range from severe encephalopathy, to classic RTT, to non-specific MR (Couvert et al., 2001; Kankirawatana et al., 2006; Masuyama et al., 2005; Moog et al., 2003). While mutations of MECP2 have been associated with RTT, duplications in the chromosomal region where MECP2 is located were shown to be related to neurological disorders associated with MR, suggesting that MECP2 is a critical dosage-sensitive gene (del Gaudio et al., 2006; Smyk et al., 2008).
Rett syndrome (RTT) is an X chromosome-linked neurodevelopmental disorder associated with the characteristic neuropathology of dendritic spines common in diseases presenting with mental retardation (MR). Here, we present the first quantitative analyses of dendritic spine density in postmortem brain tissue from female RTT individuals, which revealed that hippocampal CA1 pyramidal neurons have lower spine density than age-matched non-MR female control individuals. The majority of RTT individuals carry mutations in MECP2, the gene coding for a methylated DNA-binding transcriptional regulator. While altered synaptic transmission and plasticity has been demonstrated in Mecp2-deficient mouse models of RTT, observations regarding dendritic spine density and morphology have produced varied results. We investigated the consequences of MeCP2 dysfunction on dendritic spine structure by overexpressing (∼ twofold) MeCP2-GFP constructs encoding either the wildtype (WT) protein, or missense mutations commonly found in RTT individuals. Pyramidal neurons within hippocampal slice cultures transfected with either WT or mutant MECP2 (either R106W or T158M) showed a significant reduction in total spine density after 48 h of expression. Interestingly, spine density in neurons expressing WT MECP2 for 96 h was comparable to that in control neurons, while neurons expressing mutant MECP2 continued to have lower spine density than controls after 96 h of expression. Knockdown of endogenous Mecp2 with a specific small hairpin interference RNA (shRNA) also reduced dendritic spine density, but only after 96 h of expression. On the other hand, the consequences of manipulating MeCP2 levels for dendritic complexity in CA3 pyramidal neurons were only minor. Together, these results demonstrate reduced dendritic spine density in hippocampal pyramidal neurons from RTT patients, a distinct dendritic phenotype also found in neurons expressing RTT-associated MECP2 mutations or after shRNA-mediated endogenous Mecp2 knockdown, suggesting that this phenotype represent a cell-autonomous consequence of MeCP2 dysfunction.

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Case reportClassic Rett syndrome in a boy with R133C mutation of MECP2

Abstract

Introduction

Section snippets

Case report

Methods

Results

Discussion

Brain Dev

Am J Hum Genet

Am J Hum Genet

Fed Eur Biochem Soc Lett

Brain Dev

Cell

Brain Dev

On an unusual brain atrophy syndrome in hyperammonemia in childhood (in German)

Wien Med Wochenschr

Case report
Classic Rett syndrome in a boy with R133C mutation of MECP2