The patient first presented for clinical evaluation at 11 months of age when she was unable to sit without support and did not control her head nor speak any words; the weight and occipito-frontal circumference (OFC) were 8 kg (10th centile) and 44 cm (25th centile), respectively. Her first electroencephalogram (EEG) at 19 months showed increasing theta activity during the awake period but without any seizure. However, at the age of 4 years and 6 months, seizures were captured during video-EEG monitoring and were classified as atypical absence seizures. Subsequently, the patient became seizure free with levetiracetam, and treatment was withdrawn at ~5 years old. However, the patient developed focal seizure with five similar attacks altogether at 7 years and 2 months of age, without motor or language functional regression. Then, she received levetiracetam again after abnormal interictal video-EEG presentations (Supplementary Figure 1, EEG), and was seizure free following daily administration of 5 mg/kg levetiracetam for 3 months.
The patient has shown severe motor and speech delay since infancy, but overall, there has been slow but forward developmental progress. She did not show a social smile until 8 months. Her motor milestones were delayed profoundly, as she developed head control at 12 months, sitting at 18 months, learning to walk at 3 years and 2 months, walking without support at 5 years and running at 6 years slowly with persistent clumsiness. Language acquisition was also obviously delayed but without regression. She said her first words at ~2 years and 4 months, and at 7 years and 5 months, the last visit, she was able to inarticulately express short, three-word sentences. The patient did not present typical autistic-like features, but she was easily agitated and hyperactive, screaming and crying gratuitously, with temper outbursts, intermittent aggressiveness, and exaggerated movements or gestures at times. Moreover, sleep disturbances that consisted of night awaking with screaming spells were observed. However, she did not receive special education services or speech/language therapy.
When on admission at 7 years and 5 months, the patient's weight was 25 kg (75th centile), with microcephaly (OFC 49 cm, <3rd centile), dysmorphic features (brachycephaly, a flat face, a thin upper lip, low-set ears; Figure 1A), high-arched palate, wide-based gait, precocious puberty, and mild lower extremity hyperreflexia. Hand stereotypies were frequently observed, presenting as slow fine finger and rapid alternating movements and hand wringing.
We performed electrocardiogram (ECG), cardiac ultrasound (CUS), and metabolic testing, including plasma amino acids and acylcarnitines, urinary organic acid analysis, serum creatine kinase, biotinidase activity, folate, homocysteine, copper, blood lactate, and ammonia, all without abnormalities. Her auditory evoked potential was normal. At 7 years and 2 months, testing using the Chinese Revision of the Wechsler Intelligence Scale for Children (WISC)-III showed verbal, performance and full-scale IQ scores of 51, 59, and 51, respectively. Her brain magnetic resonance imaging (MRI) scan at the age of 7 years showed a reduced volume of the bilateral hippocampus, suggesting hippocampus atrophy, with enlargement of the lateral ventricles and peculiar temporal horn dilatation (Figure 2).