Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2)

Abstract

Mutations in the MECP2 (methyl-CpG-binding protein 2) gene are known to cause Rett syndrome, a well-known and clinically defined neurodevelopmental disorder. Rett syndrome occurs almost exclusively in females and for a long time was thought to be an X-linked dominant condition lethal in hemizygous males. Since the discovery of the MECP2 gene as the cause of Rett syndrome in 1999, MECP2 mutations have, however, also been reported in males. These males phenotypically have classical Rett syndrome when the mutation arises as somatic mosaicism or when they have an extra X chromosome. In all other cases, males with MECP2 mutations show diverse phenotypes different from classical Rett syndrome. The spectrum ranges from severe congenital encephalopathy, mental retardation with various neurological symptoms, occasionally in association with psychiatric illness, to mild mental retardation only.

We present a 21-year-old male with severe mental retardation, spastic tetraplegia, dystonia, apraxia and neurogenic scoliosis. A history of early hypotonia evolving into severe spasticity, slowing of head growth, breathing irregularities and good visual interactive behaviour were highly suggestive of Rett syndrome. He has a de novo missense mutation in exon 3 of the MECP2 gene (P225L). The clinical spectrum and molecular findings in males with MECP2 mutations are reviewed.

Introduction

Rett syndrome (RTT, MIM ∗312750) is a progressive neurodevelopmental disorder occurring almost exclusively in females. After an apparently normal development until 6–18 months of age, girls with classical RTT show regression with deceleration of head growth and loss of speech and acquired motor skills, in particular purposeful hand use. They develop stereotypic hand movements, breathing irregularities, ataxia and seizures. After a period of pseudo-stabilization and then further deterioration, the condition is mostly characterized by severe mental retardation with a relatively spared and often remarkable visual communicative ability, a progressive scoliosis and a variable degree of spasticity and rigidity often leading to wheelchair dependency. Clinical diagnosis is made in accordance with recognized criteria [1]. Apart from classical RTT, a forme fruste, a variant with preserved speech, cases with late onset of regression and congenital onset variants are known to occur in females.

In 1999, RTT was reported to be caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2) located at chromosome Xq28 [2]. RTT had been thought to be an X-linked dominant condition leading to prenatal death in hemizygous males. In recent years, however, MECP2 mutations have also been reported in males. These males may present with an RTT phenotype when they have X-chromosome aneuploidy or somatic mosaicism for the mutation. However, when MECP2 mutations occur in non-mosaic form and in chromosomally normal males, they lead to various neurological phenotypes different from RTT. We present a 21-year-old male with severe mental retardation and a neurological disorder with features reminiscent of RTT in whom a de novo MECP2 mutation was found, and a review reporting male patients with a MECP2 mutation.