Elsevier

Pediatric Neurology

Volume 41, Issue 3, September 2009, Pages 187-191
Pediatric Neurology

Original Article
Neurologic Aspects of MECP2 Gene Duplication in Male Patients

https://doi.org/10.1016/j.pediatrneurol.2009.03.012Get rights and content

Duplications in Xq28 involving the methyl CpG binding protein 2 gene (MECP2) have been described in male patients with severe mental disability, delayed milestones, absence of language, hypotonia replaced by spasticity and retractions, and recurrent and often severe infections. In a study involving five patients in two families, multiplex ligation-dependent probe amplification was used to screen the Xq28 region that includes MECP2, focusing on the presence of gene duplications. Some manifestations of the disease observed in these patients may occur less regularly than the classical abnormalities. Epilepsy with frequent seizures of the myoclonic-astatic type was observed in these patients and was associated with a slowing of the background electroencephalographic activity, rather than the generalized spike-waves or polyspike-waves usually observed in this type of seizure. In addition, cerebral abnormalities were observed with magnetic resonance imaging that were inconstant and nonspecific but that could nonetheless assist in diagnosis of this genetic pathology.

Introduction

Mutations in the methyl CpG binding protein 2 gene (MECP2) are found in more than 95% of patients with typical Rett syndrome (OMIM 300005), a progressive neurodegenerative disorder that affects almost exclusively females [1], [2]. Point mutations in MECP2 behave similarly to a complete deletion of the coding sequence of MECP2, indicating that there is complete or partial loss of functional alleles [3]. These point mutations cause features characteristic of Rett syndrome in females; in males, however, the same point mutations may result in severe encephalopathy and early death. The phenotype of MECP2 mutations in males covers a larger spectrum of neurodevelopmental disorders than would expected based on the female phenotype, varying from severe early-onset encephalopathy to moderate and isolated mental retardation [4], [5], [6], [7], [8], [9], [10], [11], [12]. Large cohort studies have demonstrated that these mutations in males are far more rare than initially thought [13].

Array comparative genomic hybridization has become the method of choice for the detection of microdeletions and more specifically for microduplications that were previously undiagnosed by classical polymerase chain reaction and Southern blot techniques [14], [15], [16], [17]. MECP2 gene duplications that were undiagnosed until recently seem to correspond to an important cause of X-linked mental disability in males, and they seem to have a phenotype different from those with MECP2 deletion.

Described here are the clinical aspects of these gene duplications in five patients from two families, with particular attention to epilepsy and neuroimaging abnormalities observed in most of these patients, especially over a long period of follow-up.

Section snippets

Case Reports

In the first four cases presented, the patients are related: an uncle and three nephews. The fifth case is from an unrelated family. In all five cases, no respiratory infection or serious infectious disease was observed during the period of follow-up.

Genetic Studies

For the first four patients, a commercially available multiplex ligation-dependent probe amplification kit was used (MRC Holland, Amsterdam, Netherlands), with methods as reported by Lugtenberg et al. [19]. The Xq28 duplication in this family had a minimum size of 260 kb including the L1CAM, IRAK1, and MECP2 genes. The grandmother and her three daughters (one of whom had three miscarriages) had the MECP2 duplication, as did all four patients. Patient 5 was investigated in another laboratory,

Discussion

In 1997, Pai et al. [20] described a large, four-generation family with five affected males and 10 carrier females with linkage to Xq28. The affected males all presented with severe mental retardation. Seizure activity occurred in four of the five affected boys, but no specific electroencephalographic pattern was noted. Subsequently, a second family with linkage to Xq28 was reported by Lubs et al. [21]. This three-generation family had five affected males presenting with severe mental

Conclusion

Some studies indicate that MECP2 duplication in males could correspond to approximately 2% of the etiologies of X-linked mental disabilities [20]. In these cases, some nonconstant but important signs that can evoke the possibility of a MECP2 gene duplication include the clinical and electroencephalographic characteristics of epilepsy when seizures occur and the frequency of nonspecific cerebral MRI abnormalities. Because the extent of MECP2 duplication varies from one patient to another, and

References (25)

  • T. Kleefstra et al.

    De novo MECP2 frameshift mutation in a boy with moderate mental retardation, obesity and gynecomastia

    Clin Genet

    (2002)
  • H.G. Yntema et al.

    In-frame deletion in MECP2 causes mild nonspecific mental retardation

    Am J Med Genet

    (2002)
  • Cited by (37)

    • Electroencephalographic and epilepsy findings in mecp2 duplication syndrome. A family study

      2019, Brain and Development
      Citation Excerpt :

      Age at seizure-onset is variable ranging from 4 to 13 years, sometimes occurring only during the second decade of life. As a matter of fact, over 90% of affected patients who survive into adolescence has seizures [3]. GTCS are the most often described seizure type, but tonic, atonic, absence and atypical absence, partial complex, reflex, myoclonic and myoclonic-astatic seizures have also been observed [3–6].

    • Successful corpus callosotomy for post-encephalopathic refractory epilepsy in a patient with MECP2 duplication syndrome

      2019, Brain and Development
      Citation Excerpt :

      Cardinal phenotypes of MECP2 duplication syndrome include hypotonia, global developmental delay, recurrent respiratory infections, epilepsy, and gastrointestinal symptoms [3]. Nearly 50% of affected individuals develop epilepsy, and both generalized and focal seizures are often refractory despite active treatment with multiple antiepileptic medications [3–5]. To our knowledge, no previous reports have discussed the efficacy of surgical treatment for seizures in patients with MECP2 duplication syndrome.

    • Copy number variants in adult patients with Lennox-Gastaut syndrome features

      2013, Epilepsy Research
      Citation Excerpt :

      A peculiar electroclinical pattern has recently been described. Seizures with atonic and myoclonic components are characteristic (Vignoli et al., 2012), sometimes suggestive of epilepsy with myoclonic–astatic seizures of Doose (Echenne et al., 2009), or the myoclonic variant of LGS, as in our patient. EEG usually demonstrates generalized slow spike and wave (Vignoli et al., 2012).

    View all citing articles on Scopus
    View full text