Expanding phenotype of p.Ala140Val mutation in MECP2 in a 4 generation family with X-linked intellectual disability and spasticity

doi:10.1016/j.ejmg.2016.07.003

European Journal of Medical Genetics

Volume 59, Issue 10, October 2016, Pages 522-525

https://doi.org/10.1016/j.ejmg.2016.07.003 Get rights and content

Abstract

Mutations in MECP2 (MIM #312750), located on Xq28 and encoding a methyl CpG binding protein, are classically associated with Rett syndrome in female patients, with a lethal effect in hemizygous males. However, MECP2 mutations have already been reported in surviving males with severe neonatal-onset encephalopathy, or with X-linked intellectual disability associated with psychosis, pyramidal signs, parkinsonian features and macro-orchidism (PPM-X syndrome; MIM3 #300055).

Here we report on the identification of the p.Ala140Val mutation in the MECP2 gene in 4 males and 3 females of a large Caucasian family affected with X-linked intellectual disability. Females present with mild cognitive impairment and speech difficulties. Males have moderate intellectual disability, impaired language development, friendly behavior, slowly progressive spastic paraparesis and dystonic movements of the hands. Two of them show microcephaly.

The p.Ala140Val mutation is recurrent, as it was already described in 4 families with X-linked mental retardation and in three sporadic male patients with intellectual disability. We further delineate the phenotype associated with the p.Ala140Val mutation, illustrating a variable expressivity even within a given family, and we compare our patients with previous reported cases in the literature.

Introduction

The MECP2 gene, which is located on Xq28 and encodes the methyl CpG-binding protein 2, haA140s been reported as both a repressor and an activator of several target genes, and plays an essential role in brain development (Chahrour et al., 2008). Mutations in the (MECP2) gene were identified since 1999 in females affected with Rett syndrome. The typical clinical course of this severe neurological disorder consists of a normal neonatal period followed by loss of acquired skills and deceleration of head growth between 6 and 18 months, leading to severe intellectual disability and behavioral problems (autism, stereotypic hand movements). Rett syndrome is a X-linked dominant disorder, which affects almost exclusively females because of lethal effect of mostly mutations in hemizygous males.

However, missense, frameshift and nonsense mutations in MECP2 were also reported in males with cognitive impairment, and could be responsible for up to 1.7% of X-linked intellectual disability (Villard, 2007, Winnepenninckx et al., 2002). Affected male patients present with a wide spectrum of neurological disorders, ranging from severe neonatal encephalopathy to non specific intellectual deficiency, occasionally associated with parkinsonism, pyramidal signs, psychiatric symptoms and macro-orchidism (PPM-X phenotype) (Villard, 2007). Regression of the acquired skills and arrest of brain development are not specific features in males with a mutation in the MECP2 gene. In particular, there is no deterioration of the language abilities, which are altered from early stages of development.

Section snippets

Clinical report

The Caucasian family comprises 4 generations, with 5 males and 5 females presenting with intellectual disability (Fig. 1a). Seven of them (4 males and 3 females) were referred to our Center for Human Genetics for clinical evaluation. We obtained written informed consent from the patients and/or their legal guardian for molecular studies and the publication of their clinical photographs.

Patient III.5 was born at term of an uneventful pregnancy, with normal birth parameters. His psychomotor

Discussion

We report on the identification of the p.Ala140Val mutation in the MECP2 gene in 4 males and 3 females of a large family affected with X-linked intellectual disability. The alanine in position 140 of MECP2 is located within the α –helix of the methyl-CpG binding domain (MBD) and is a highly conserved nucleotide across species. The MBD of MeCP2 binds to methylated CpG sites in the genome and inactivates the expression of target genes by condensing the chromatin structure, blocking

Acknowledgments:

We would like to thank the patients and their family for their participation, and the “Fonds Marguerite-Marie Delacroix” for the research grant provided to S.M.

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Citation Excerpt :
Nevertheless, somatic mosaicism could not be ruled out in those patients. PPM-X was identified in 8 unique families, with 24 affected male patients aged from 11 to 67 years old (see suplemental material - Table 3) [41,54–60]. The intellectual deficiency was seen in all patients, whereas motor signs (e.g., spasticity and/or parkinsonism) were reported in 23 patients.
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.
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Expanding phenotype of p.Ala140Val mutation in MECP2 in a 4 generation family with X-linked intellectual disability and spasticity

Abstract

Introduction

Section snippets

Clinical report

Discussion

Acknowledgments:

Am. J. Hum. Genet.

FEBS Lett.

Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2

Nat. Genet.

MeCP2, a key contributor to neurological disease, activates and represses transcription

Science

MECP2 mutation in a boy with language disorder and schizophrenia

Am. J. Psychiatry

MECP2 is highly mutated in X-linked mental retardation

Hum. Mol. Genet.