
Epilepsy-aphasia spectrum (EAS) disorders present with seizures, abnormal electroencephalogram (EEG) results, usually in combined with cognitive and behavioral impairments [1]. Previously, these EAS disorders were thought to involve problems with the immune system, and high-dose steroids were usually used for treatment [2]. However, recent studies have investigated the genetic basis of the condition, and have identified mutations in
The NMDA receptor is a neurotransmitter-gated ion channel, comprised of two glycine-binding GluN1 subunits encoded by
The clinical spectrum of
A female patient was born at 39 weeks of gestation by vaginal delivery, after a normal pregnancy with no birth injury, she was the second child in her family. At birth, her height and weight were within normal limits.
She was first diagnosed as suffering from congenital hypothyroidism. When she was three-weeks old, she was taken to hospital because of neonatal jaundice; her total serum bilirubin was high, at 17.8 mg/dL. Photo therapy was administered, and total bilirubin returned to normal. A thyroid function test revealed a slightly elevated level of thyroid stimulating hormone (TSH). None of her family members have thyroid related disease, and her initial TSH level measured during neonatal screening test was normal. When she was one-month-old and weighting 5.6 kg, we followed up her thyroid hormone levels and found that her TSH was still above 5 μIU/mL (TSH 8.61 μIU/mL, free T4 1.42 ng/dL, T3 127.94 ng/dL). Thyroid ultrasonography showed a normal position and appearance of the thyroid gland, but Tc-99m thyroid scan uptake was low at 0.8% (normal range, 0.3-3.0%). Since the patient needed thyroid hormone replacement, we started to treat her with levothyroxine (30 mcg/day). After three years of medication, we re-evaluated her thyroid function, and the levels of TSH and free T4 were normal, so treatment was discontinued. However, two years later, thyroid function tests showed low free T4 level at 0.58 ng/dL and she was restarted on levothyroxine. This condition was distinct from transient primary congenital hypothyroidism, which usually recovers to euthyroidism within the first years of life.
Epilepsy was another feature that needed treatment. Although the results of her neonatal screening test were all normal, at four years old, a febrile seizure event occurred, with generalized tonic movement, and after then, unprovoked seizure events followed at least twice a year. Those events were characterized with focal seizures restricted to both arms which usually developed as secondary generalized tonic seizures. Serial EEG tests and brain magnetic resonance imaging (MRI) were administered. The EEG results consistently showed moderately abnormal sleep records due to a few small spike discharges, dominantly in the fronto-centro-temporal areas, and she was prescribed anti-epileptic drugs. Oxcarbazepine (Trileptal®; Novartis international AG, Basel, Switzerland), the first drug she tried, was not effective as she continued to have focal seizures, and topiramate (Topamax®; Novartis international AG) was therefore added. The frequency of seizures decreased significantly, and she was seizure-free for over two years. Spikes in the EEG were still observed (Fig. 1), leading us to closely monitor her symptoms. An initial brain MRI showed no abnormal findings, but in follow-up, a small Rathke’s cleft cyst was found, and was suspected as to be an incidental finding (Fig. 2).
Her developmental was also evaluated. When she was seven years old, her height was 129.0 cm (50-75 percentile) and weight was 27.2 kg (25-50 percentile), within normal ranges. However, a slow decline in growth velocity was apparent. A combined pituitary functions test—a method for simultaneously assessing the hypo-function of the anterior pituitary hormones (GH, adrenocorticotropic hormone [ACTH], follicle-stimulating hormone [FSH], luteinizing hormone [LH], TSH, and prolactin)—measured her peak GH level as 2.2 ng/mL which was under 10 ng/mL, raising the possibility of a GH deficiency. Another follow-up GH stimulation test with L-dopa and arginine also resulted in a diagnosis of GH deficiency, and we decided to add recombinant GH replacement to catch up with her expected growth pattern. Her receptive and expressive language, and social development was also delayed by about two years, although her motor developments met standard milestones and was appropriate for her age. In consultation with a psychiatrist, we found her intelligence quotient to be 71 and memory quotient to be 76, suggesting borderline intellectual disability.
To investigate further, we carried out genetic analysis using diagnostic exome sequencing of the patient, and Sanger sequencing of her unaffected parents. For diagnostic exome sequencing, genomic DNA was extracted from EDTA whole blood and all exons of 5,447 genes captured using a Celemics G-Mendeliome DES Panel. The post-capture library DNA was subjected to sequence analysis and the sequence reads were mapped and compared with the published human genome build (UCSC GRCh37 or hg19 reference). We found that the patient has a missense and a nonsense mutation in
EAS disorders, which are characterized by epilepsy and developmental delay, have only been understood as arising from autoimmune system failure [3]. However, with discovery of
The relationships between mutations in this gene and non-neurological symptoms are not well understood, and the testing available for these patients is limited. No phenotypes arising from mutations in
By presenting this case, we raise questions about the phenotypic spectrum of
In conclusion, patients with EAS disorders caused by
The authors declare that they do not have any conflicts of interest.
![]() |
![]() |