Background: Next-generation sequencing can often be used to etiologically clarify previously unclear neuropediatric conditions. In some male and female patients, mutations in the gene IQSEC2, located on chromosome Xp11.22, could be described as the cause of X-linked mental retardation 1 (MRX1). IQSEC2 encodes a GTP exchange factor and regulates its binding to the ADP-ribosylation factor 6 in excitatory glutamatergic synapses and plays a relevant role during the development of neuronal dendrites. We present the case of a 4-year-old female patient with MRX1, in which a previously unreported de novo mutation in IQSEC2 was identified.
Objectives: Our goal was to elucidate the etiology of our patient’s global developmental disorder and epilepsy. This case report aims to sensitize for the study of IQSEC2 in patients with a similar phenotype.
Question: We describe the case of a 4-year-old girl of nonconsanguineous healthy parents of Turkish descent. Inconspicuous pregnancy and birth history, at 12 months of age, first appearance with us due to motor developmental delay with marked muscular hypotension and complex focal epileptic seizures with secondary generalization. Notable were prominent, widened halluces and long, narrow fingers. The first cranial magnetic resonance imaging at the age of 14 months showed a global atrophy of the brain, but no further abnormalities were found. Interictal EEGs were repeatedly inconspicuous. Despite extensive clarification, the etiology was initially unclear. The patient initially became seizure-free with levetiracetam and sultiame, but was significantly retarded in her development. At the age of 3 years, recurrent complex-focal seizures and absences occurred, with interictal EEGs remaining relatively unremarkable. The switch to the current treatment with valproate, sultiame, and mesuximide finally led to seizure freedom after several months.
Methods: To clarify the suspected genetic etiology, an unremarkable chromosome analysis, an array CGH, and a Sanger sequencing of MECP2 and FMR1 were first performed in our patient. Later, the diagnosis was finally supplemented by an epilepsy panel.
Results: A heterozygous de novo variant in IQSEC2 (c.1591C>T;p.Arg531*) was identified by the epilepsy panel. This leads to a stop codon and thus most likely to a nonsense-mediated mRNA decay. Since other stop variants have already been described as causally related to epileptic encephalopathy, the variant is most likely the cause of the disease.
Conclusion: De novo nonsense mutations in IQSEC2 may be the cause of isolated mental retardation in males and more rarely of severe developmental disorders and epilepsy in both sexes. Our case shows that even in girls, IQSEC2-associated X-coupled mental retardation must be considered.
