A 38-year-old male was admitted to the Department of Epilepsy due to memory decline and seizure. One and a half years ago, the patient developed short-term memory decline without obvious causes. He could not remember what he planned to buy and forgot to pay bills. He did not pay attention to the symptoms and visit doctor. Eight months ago, his recent memory declined rapidly indicated by forgetting what he had just said, compromised abilities of planning and arrangement, and restricted capacity to reasonably dispatch employees. He had long-term memory preserved, and no disorientation, dyscalculia, difficulty finding words or comprehension disturbance. His basic and instrumental abilities of daily living were unaffected. Cranial magnetic resonance imaging (MRI) from local hospital suggested a mildly widened bilateral frontal-parietal sulcus. Ten days ago, he experienced a generalized tonic-clonic seizure manifested as loss of consciousness, limb convulsions, and urinary incontinence, and regained consciousness after 2 minutes. Reexamination of cranial MRI showed no new abnormalities. Cerebrospinal fluid (CSF) results displayed no abnormalities in pressure, routine, biochemical, pathogenic or autoimmune antibody profiles. He was given levetiracetam 0.25g twice daily and lamotrigine 25mg twice daily to control seizure. Four days ago, he had a seizure again during antiepileptic drugs treatment, and his short-term memory was further declined. The patient had a history of head scalp abrasion without any symptoms. His biological parents, one sister and one brother were healthy. He denied a history of familial diseases. Neurological examination was normal except the compromised short-term memory, attention, executive function and visuospatial ability.
After hospitalization, Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scales were used to evaluate overall cognitive function, with scores of 15/30 points for both, suggesting memory, attention, executive function and visuospatial ability impairments. Clinical Dementia Rating (CDR) scale was used to evaluate the severity of disease, with a score of 0.5/3, indicating mild cognitive impairment (Fig. 1d).
Whole exome sequencing revealed a missense pathogenic variant in presenilin 1 (PSEN1) c.617G > A, (p.Gly206Asp), which was predicted to be pathogenic by the population database (rs63750082, gnomAD 0.0008%), and the evidence for its pathogenicity was sufficient, but was not found in his parents, one sister, and one brother. Simultaneously, the patient carried a missense mutation in potassium voltage-gated channel subfamily Q member 2 (KCNQ2) c.1490G > A p.(Arg497His), which was also found in his parents, one sister, and one brother (Fig. 1a). This KCNQ2 mutation exists in population database (rs769414365, gnomAD 0.0009%), has an uncertain clinical significance predicted by American College of Medical Genetics and Genomics, and is not reported in HGMDpro database.
CSF results showed decreased Aβ1−42 and Aβ1−40 levels, and increased phosphorylated tau and total tau levels (Table S1). Long-term video electroencephalogram displayed slow waves in frontal and temporal regions without epileptiform discharges in the hospitalization and nine months after treatment (Fig. S1). Cranial MRI presented bilateral hippocampal atrophy, with the scores of medial temporal atrophy of 1 and 2 for the left and right hippocampus, respectively (Fig. 1b). 18F-fluorodeoxy glucose-positron emission tomography (PET) implied decreased glucose metabolism in bilateral temporal, parietal and occipital lobes. 11C-Pittsburgh compound B-PET and 18F-flortaucipir-PET suggested diffuse depositions of Aβ and tau in cortex (Fig. 1c). Other laboratory tests showed no abnormalities.
In addition to the antiepileptic drugs, the patient was given sodium oligomannate 450mg twice daily to improve cognitive function given the potential for cholinesterase inhibitors to worsen seizures. Two weeks, 6 and 9 months after discharge, his seizure was completely controlled and cognition was significantly improved. The MMSE scores increased by 9 points, which referred to 4 points in orientation, 1 point in recent memory and 4 points in language. The MoCA scores increased by 8 points, which referred to 1 point in executive function and visuospatial ability, attention and language, 2 points in delayed recall and 3 points in orientation, respectively,6 months after discharge. MMSE score was further improved by 1 point in short-term memory 9 months after discharge, and the scores of MoCA and CDR scales remained stable, indicating a sensitive, substantial and sustained response of the patient to the medications used (Fig. 1d).