MECP2-Related Disorders in Males

Abstract

Methyl CpG binding protein 2 (MECP2) is located at Xq28 and is a multifunctional gene with ubiquitous expression. Loss-of-function mutations in MECP2 are associated with Rett syndrome (RTT), which is a well-characterized disorder that affects mainly females. In boys, however, mutations in MECP2 can generate a wide spectrum of clinical presentations that range from mild intellectual impairment to severe neonatal encephalopathy and premature death. Thus, males can be more difficult to classify and diagnose than classical RTT females. In addition, there are some variants of unknown significance in MECP2, which further complicate the diagnosis of these children. Conversely, the entire duplication of the MECP2 gene is related to MECP2 duplication syndrome (MDS). Unlike in RTT, in MDS, males are predominantly affected. Usually, the duplication is inherited from an apparently asymptomatic carrier mother. Both syndromes share some characteristics, but also differ in some aspects regarding the clinical picture and evolution. In the following review, we present a thorough description of the different types of MECP2 variants and alterations that can be found in males, and explore several genotype–phenotype correlations, although there is still a lot to understand.

Genetic analysis of a pedigree with MECP2 duplication syndrome in China

“…The diseases related to protein gain of function (GOF) caused by MECP2 gene duplication were mainly male, accounting for about 90.3% of the total [14]. 80% of MDS gene variants are inherited from asymptomatic mothers, but these repetitive gene segments can change throughout inheritance [15,16].…”

Inhibitory Synaptic Influences on Developmental Motor Disorders

“…By 4–7 years old, children with Rett syndrome have motor and cognitive deficits that will continue throughout their lifespan [ 203 ] in addition to a variety of neurobehavioural issues consistent with autism [ 203 ]. There is a direct genetic link for Rett syndrome, a mutation in the X-linked MECP2 gene [ 205 ], with females overwhelmingly more likely to be affected [ 203 , 206 ]. The MECP2 gene is highly expressed in neurons and is essential for neuronal development and in the establishment of synaptic connections [ 207 ], with normal function involving both repression (via binding to methylated DNA) or activation of gene transcription [ 208 ].…”

“…However, in Rett syndrome there are many individual MECP2 mutations, neither necessary nor sufficient for diagnosis [ 211 , 212 ]. Males that are affected develop the syndrome extremely rapidly (within a few days postpartum) and die within 2 years [ 206 , 213 ]. Recently, there have been major advancements in the amelioration of Rett syndrome via growth factors (IGF1), MECP2 gene transfer, genetic corrections and approaches focusing on downstream targets in rodent models and human trials [ 207 , 214 , 215 , 216 , 217 , 218 , 219 ].…”

Early life stress exacerbates behavioural and neuronal alterations in adolescent male mice lacking methyl-CpG binding protein 2 (Mecp2)

“…An increasing amount of evidence suggest that Mecp2 has a role on the susceptibility to early life environmental disturbances and thus on determining the coping strategies that animals develop later in life ( Abellán-Álvaro et al, 2021 ; Sánchez-Lafuente et al, 2022 ). Dosage-variation on functional MECP2 during human neurodevelopment have been described in RTT, predominantly affecting females ( Amir et al, 1999 ), but also affecting males in MDS ( D’Mello, 2021 ; Pascual-Alonso et al, 2021 ) and in cases of somatic mosaicism and intellectual disability associated with RTT ( Orrico et al, 2000 ; Kudo et al, 2002 ; Topçu et al, 2002 ; Venâncio et al, 2007 ). In the case of patients, these early life environmental disturbances are even more complicated to assess due to additional motor disabilities and communication impairments among other phenotypical manifestations.…”

“…Nonetheless, MECP2 mutations have also been identified in male patients with intellectual disabilities ( Orrico et al, 2000 ; Kudo et al, 2002 ), as well as cases of somatic mosaicism associated with RTT ( Topçu et al, 2002 ; Venâncio et al, 2007 ). Additionally, MECP2 duplication syndrome (MDS), which only manifests in males, is characterised by intellectual disability, heightened anxiety-like behaviours, seizures, and recurrent respiratory infections among others ( D’Mello, 2021 ; Pascual-Alonso et al, 2021 ). The plethora of MECP2 -related disorders demonstrates that this gene occupies a central role in the post-natal development of the brain in both sexes.…”