Original articleIdentification of MeCP2 mutations in a series of females with autistic disorder
Introduction
In its classic form, Rett disorder (RTT, MIM312750) is an X-linked disorder characterized by normal neurologic development until 6 to 18 months of age, followed by a progressive developmental regression. RTT occurs almost exclusively in females. Incidence rates range from 0.25 to 1 in 10,000 female births [1], [2]. Skjeldal et al. [3] reported a rate of 2.17 in 10,000 female births when the full spectrum of RTT syndrome variants was included. Developmental regression is followed by a deceleration of head growth, loss of purposeful hand movements, and followed by the appearance of midline, stereotypic hand movements [4]. Additional features observed in RTT patients include seizures, ataxia, hyperventilation, and social communication problems. These social engagement problems are similar to those observed in autistic disorder (AutD) and therefore can result in an initial misdiagnosis of AutD in some RTT patients [5]. Usually the appearance of the additional findings seen in RTT (Table 1) clarifies the diagnosis in these patients. Atypical RTT involves variations from the characteristic RTT profile in age of onset, sequence, and severity or presence of expected features. Consistently identified atypical groupings include congenital, forme fruste, and preserved speech variant, as well as other rare variants [6].
In 1999, Amir et al. [7] demonstrated that mutations in the X chromosome gene methyl-CpG-binding protein 2 (MeCP2) cause the majority of cases of RTT. The MeCP2 protein binds methylated cytosine residues, eventually leading to transcriptional repression [8]. Subsequent studies have found over 60 unique mutations in MeCP2, with mutations noted in 80-100% of RTT patients [9], [10], [11], [12]. As previously mentioned, until recently RTT had only been observed in females and was believed to be lethal in males. However, since the identification of MeCP2 as the gene defect, two males with RTT have been reported [13]. In addition, increasing evidence points to a wider range of severity and heterogeneity of phenotype [14], [15], [16], [17]. Further, Hammer et al. [18] indicate that MECP2 mutations result in a much broader clinical presentation than those encompassed under the RTT spectrum. In contrast to RTT, AutD occurs more frequently in males, with a male:female ratio of 4:1 [19]. However, studies have failed to demonstrate X chromosome linkage as a major genetic etiology for idiopathic AutD [20]. A study of the MECP2 gene in a small mixed gender group of children with AutD failed to detect any mutations or polymorphisms [21]. This failure led the investigators to conclude that MECP2 coding sequences are not an important factor in autism. However, the small number of females in the study limits the findings. The purpose of the present study was to screen a larger number of females diagnosed with AutD for mutations in the MeCP2 gene.
Section snippets
Family studies and patient evaluation
Two hundred and eighty-nine AutD patients from sporadic (one) individual affected in a family and no family history of AutD) and multiplex (two) or more individuals with AutD in a family) families were ascertained to identify AutD genetic risk factors. Sixty-nine of these patients were female. Individuals included in this study were between 3 and 21 years of age and had a pre-existing clinical diagnosis of AutD. Medical records were reviewed to confirm the medical and developmental history for
Results
Mutations in MeCP2 were found in two of the 69 AutD females studied. Neither patient meets all of the current diagnostic criteria for RTT (Table 1), based on the Rett Syndrome Diagnostic Criteria Work Group [33].
Discussion
Mutations in the MeCP2 gene were identified in two females (ages 10 and 16) who meet criteria for the diagnosis of AutD. The diagnosis of AutD in these patients was confirmed using the ADI-R. This psychometric instrument is the current “gold standard” for diagnostic confirmation in all ongoing genetic linkage studies for AutD [29], [42], [43], [44], [45].
Neither of these patients evaluated exhibit the classic RTT features [4]. The possibility of a RTT variant [46], [47] was examined given the
Conclusion
These data suggest that the phenotype associated with MeCP2 mutations is highly variable, and that individuals with MeCP2 mutations can present with a milder clinical phenotype such as AutD. Thus, in some cases, MeCP2 testing may be warranted for females presenting with AutD, especially those presenting with any associated symptoms of RTT.
Acknowledgments
We would like to thank the autism patients and their families for their participation, without which this research would have been impossible. This work was supported in part by NIH Program Project Grant NS26630, NIH R01 Grants HD36701 and NS36768, and the National Alliance of Autism Research (NAAR) through a gift from Audrey Flack and H. Robert Marcus.
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