An ASD "comorbidity" can have several fundamentally-distinct causal origins: it can arise due to shared genetic risk between ASD and non-ASD phenotypes (e.g., ASD and microcephaly in the context of the MECP2 mutation), as a "secondary symptom" of ASD when engendered by the same causal influence (e.g., epilepsy in channelopathies associated with ASD), due to chance co-occurrence of ASD with a causally-independent liability (e.g., ASD and diabetes), or as the late manifestation of an independent causal influence on ASD (eg, attention-deficit/hyperactivity disorder).
In 2009, four families with a distal duplication of Xq28 not including MECP2 and mediated by low-copy repeats (LCRs) designated "K" and "L" were reported with intellectual disability and epilepsy.
As a consequence of these findings SCN1A should be considered in the molecular routine screening in MECP2-negative individuals with RTT and early onset epilepsy.
Mutations in the cyclin-dependent kinase-like 5 (CDKL5) (NM_003159.2) gene have been associated with early-onset epileptic encephalopathies or Hanefeld variants of RTT(Rett syndrome).
Duplications involving the methyl-CpG-binding protein 2 gene (MECP2) locus at Xq28 have been frequently identified in male patients who exhibit a phenotype unique from that of Rett syndrome, which is mainly characterized by severe mental retardation, recurrent infections, and epilepsy.
Duplications encompassing the MECP2 gene on the Xq28 region have been described in male patients with moderate to severe mental retardation, absent speech, neonatal hypotonia, progressive spasticity and/or ataxia, recurrent severe respiratory infections, gastrointestinal problems, mild facial dysmorphisms (midface hypoplasia, depressed nasal bridge, large ears) and epilepsy.
We performed mutation screening of CDKL5 in 60 female patients who had been identified as negative for the methyl CpG-binding protein 2 gene (MECP2) mutations, but who had current or past epilepsy, regardless of the age of onset, type, and severity.
MeCP2 expression was detected in 35 temporal neocortex tissue samples from patients with intractable TLE and 14 histologically normal temporal lobe tissue samples from trauma patients without epilepsy by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry and double-label immunofluorescence.
We observed a partial MECP2 duplication in an adult male with epilepsy and mild neurocognitive impairment who was able to function independently; this phenotype has not previously been reported among males harboring gains in MECP2 copy number.
Interestingly, they did not exhibit other clinical features commonly observed in American-European patients with MECP2 duplication, including recurrent respiratory infections and epilepsy.
All patients underwent video/EEG monitoring and molecular analysis of the MECP2 gene or, in negative cases, of the CDKL5 and FOXG1 genes.The frequency of epilepsy was 79%.