Double cortex syndrome (DC; also known as subcortical laminar heterotopia) is a generalized neural migration disorder that is characterized clinically by intractable epilepsy and mental deficiency.1 In DC, a subpopulation of neurons appears to be arrested in the subcortical white matter and forms a second layer of gray matter.1 All familial DC and approximately one-third of sporadic DC cases have mutations of the doublecortin (DCX) gene in Xq22.3—q23.2,3
Abnormal neural migration patterns have recently been reported in patients with schizophrenia.4 Cytogenetic abnormalities related to schizophrenia have also been reported.5,6 It is of interest if patients with distinct cell migration abnormalities or cytogenetic alterations exhibit schizophrenia-like symptoms.
Here we report a female patient with sporadic DC who developed schizophrenia-like psychosis.
History of epilepsy and psychosis. The patient is a right-handed 39-year-old Japanese woman. Her family members (parents and two brothers) had normal cognitive functions and no neuropsychiatric disorders and have adapted themselves to the community well. She entered an ordinary elementary school, although her early developmental milestones were somewhat delayed.
At age 10, she developed complex partial seizures (CPS), characterized by aura, loss of consciousness with eye deviation to the left, occasional brief tonic movement of both arms, and subsequent generalized tonic-clonic seizures (GTC). She suffered epileptic seizures 3 to 4 times per month. Since her first seizure, she has shown a progressive mental decline, which necessitated her transfer to a special class at age 12. Since graduating from a special high school for mentally handicapped persons, she has commuted to a workshop for the disabled.
At age 25, she developed delusions of persecution and reference without any preceding explanatory psychosocial events. She had visual hallucinations of ghosts and monsters and probable auditory hallucinations. She exhibited some unusual mannerisms (walking around talking to herself and staring extendedly at photos of a popular singer) and obsessive behaviors (flushing the toilet every 15 minutes). During these episodes, her consciousness was clear and her orientation was intact. Administration of an antipsychotic drug (levomepromazine, 150 mg per day) improved her mental state within 2 months. She had three more psychotic episodes with similar symptoms, and levomepromazine was found to be effective again. Since her first psychosis occurred, the frequency of seizures has decreased to 1 to 2 times per year for the past 15 years. Her personality has not altered throughout her clinical course except during psychotic episodes. She has taken 600 mg of carbamazepine per day (serum level; 9.7 μg/ml).
Investigations. EEG showed well-developed 9-Hz to 11-Hz occipital rhythms and bilateral epileptiform discharges with predominance over the left frontotemporal region. During the four psychotic episodes, EEG has not normalized. Brain MRI revealed bilateral bands of heterotopic gray matter in the centrum semiovale, separated from cortical gray matter by layers of white matter (F1). Diffuse atrophy of the cerebral hemispheres was also observed, although the gyral and convolutional patterns of the overlying cortex were normal. The limbic structures were unremarkable. Interictal brain SPECT images with [99mTc]HMPAO have been reported elsewhere.7 Briefly, they revealed identical or increased perfusion of the subcortical laminar heterotopia, compared with that of the overlying cortex, and hypoperfusion of the left temporal lobe. Neurological examinations were unremarkable. Tanaka-Binet IQ Scale score was 38 at age 35 years.
Chromosome aberration. The patient and her mother underwent chromosomal and genetic studies after giving written informed consent. Cytogenetic examination using GTG banding revealed that the patient had a pericentric inversion of chromosome 9, a karyotype of 46XXinv(9)(p12q13). Her mother also had this chromosomal abnormality.
Mutation analysis. Genomic DNA was extracted from white blood cells. To scan regions of DCX covering the branch site of each intron and the 5′-upstream sequences of exon 1A, we determined the following sequences by using GenomeWalker Kits (Clontech, Palo Alto, CA, USA): 325 bp upstream of exon 1A and 146 bp of intron 1B 3′-portion (DDBJ/EMBL/GenBank Accession Nos.: AJ005591—AJ005597). Polymerase chain reactions (PCRs) were performed by using a Gene Amp 9700 thermal cycler (PE Applied Biosystems, Chiba, Japan) under the conditions shown in t1. PCR products were sequenced directly in both directions with a BigDye terminator kit and an ABI 377 DNA sequencer (PE Applied Biosystems). Mutations in the gene DCX were not detected in this patient or her mother.
This patient's clinical characteristics and brain MRI findings were consistent with double cortex syndrome. She developed interictal schizophrenia-like psychosis without any explanatory preceding psychosocial events.
As for an underlying genetic abnormality of this patient, we failed to detect any alterations in the DCX gene, including all possible branch point sequences in the 3′ portions of introns. To our knowledge, this is the first report to analyze extended intronic regions, including potential branch sites, to examine possible splicing-related abnormalities. In sporadic DC patients, mutations in the coding regions of DCX mutation are less frequently identified than in familial DC patients. Recent investigation3 suggested that genetic heterogeneity may exist for DC and may be explained by other types of mutations of DCX outside the regions already examined, or by mutations of other genes. In addition to further studies on genetic and structural aspects, functional neuroimagings may facilitate disclosure of the relationship between the diversity of DC and its symptoms.8
This patient had a pericentric inversion of chromosome 9 [inv(9)], probably transmitted maternally. Although inv(9) has been observed in persons without any specific phenotypes such as her mother, schizophrenic patients have this inversion more frequently than do individuals in the general population.5 Recent studies on schizophrenia revealed that the pericentric region of chromosome 9 might be associated with its pathogenesis.5,6 It is possible that the inv(9) in our patient might be associated with some vulnerability to a schizophrenia-like psychosis.
Many patients with schizophrenia have been reported to have cytoarchitectural abnormalities in brain tissues that are assumed to result from abnormal neuronal development.4 Some cytoarchitectural disturbances in our patient may be extreme compared with those seen in schizophrenic patients and may cause the serious mental dysfunction through modifications of neural pathways that resemble those of schizophrenics.
Psychiatric features of DC patients have not been well documented, except for behavioral problems such as impulsiveness, aggression, and unstable emotions. Patients with DC commonly suffer from varying degrees of mental retardation.1 This patient has showed mental decline since the first seizure occurred. Mental deterioration due to recurrent seizures has not been often observed.9 Meanwhile, in some DC patients reported,10 uncontrolled seizures together with underlying neural migration disorder appeared to result in mental decline.
People with mental retardation, especially when it is complicated by organic brain disorders, are liable to develop psychotic features.11 These psychiatric vulnerabilities are often related to a reduced capacity to cope with complex social and cognitive demands and to difficulty in solving problems.11,12 However, this patient's episodes were not simply derived from her mental disturbance, since similar psychotic symptoms occurred four times without any specific psychosocial stressors and lasted for several months each time.
Patients with epilepsy have an increased risk of developing interictal schizophrenia-like psychosis.13,14 The patient's epilepsy type (focal epilepsy) and seizure types (CPS and GTC) corresponded to the risk variables.14 However, the seizure frequency and the antiepileptic drugs administered were unremarkable around the periods of her psychotic episodes. Despite the lack of a distinct relationship between the surface EEG findings and psychotic episodes, frequent EEG discharges in the frontotemporal regions might be associated with her psychiatric symptoms. It is possible that discharges from diffuse subcortical ectopic tissues propagate irregularly. Some studies have shown that epileptiform discharges in the depth, which are not necessarily recorded in the surface EEG, possibly provoke behavioral changes including psychotic symptoms.15 Although this patient manifested prominent positive psychotic symptoms, some of her psychiatric features, such as visual hallucination and no personality change, are more consistent with those of interictal psychosis than schizophrenia.13
The co-occurrence of the abnormalities in the neural network and the cytogenetic alteration, in addition to epilepsy, may have contributed to this patient's susceptibility to schizophrenia-like psychosis. Further investigation is necessary to elucidate the mechanisms underlying the psychiatric features of patients with DC.
The authors thank Koji Saitoh and Hitoshi Nomoto for their technical assistance.