We report the case of a female patient, born after a non-eventful gestation. Prenatal ultrasounds were described as normal. She was born via cesarean at 39 weeks, with Apgar score 9/10 and appropriate birth size. Newborn screening tests and perinatal period were unremarkable. She is the only child of non-consanguineous parents and family history was non-contributory.
At 2 months old, she was admitted to the Pediatric ward due to focal clonic seizures of her left lower limb, lasting approximately 10 s, which did not cease by pressing the limb and had been occurring either during sleep or awake, two to four times a day, for at least 1 week. Laboratory blood tests including blood count, inflammatory parameters (C-reactive protein), muscle enzymes, glucose and electrolytes did not show relevant abnormalities. Electroencephalography was performed during hospital stay and revealed normal background with interictal and ictal epileptiform discharges restricted to the midline central and right central regions (Cz-P4). No structural brain anomalies were identified by neuroimaging. She was initially treated with levetiracetam 10 mg/kg/dose twice daily and frequency of seizures was reduced to one/two times a day. Levetiracetam was progressively increased to 30 mg/kg/dose, but she maintained the same periodicity of seizures. On the third week of treatment, antiseizure medication was changed to phenobarbital (3 mg/kg/day in 3 divided doses). During the following week, she presented three brief episodes of increased muscle tone in the left lower limb, lasting approximately five seconds. Since then, no more episodes of seizure were described.
At 2 years old, she was referred to the Pediatric Neurodevelopment department since she was unable to achieve the language developmental milestones for her age. She displayed an abnormal gait pattern (toe walking) since she was 20 months old. She presented difficulties on establishing eye contact, following simple instructions or responding consistently to her name. She also struggled on joint attention and symbolic play. Her speech was characterized mostly by jargon with no intelligible words. She was unable to name body parts or objects in pictures. Her mother reported an obsession with water and keyboards. According to her school daycare educator, she engaged in a more passive play with her peers. Her daycare educator also reported some difficulty with specific textures while playing. There was no history of unusual eating habits.
On physical examination, she displayed some peculiar facial features including a large mouth with widely spaced teeth. Head growth evaluation was normal, including her current head circumference. Neurological examination was unremarkable aside from toe walking. Auditory evoked potentials were performed and displayed normal results. Diagnosis of ASD was confirmed using the criteria from the Diagnostic and Statistical Manual of Mental Disorders, fifth edition [1]. She was started on multimodality interventions, namely speech-language and occupational therapies (with sensory integration approach). During her follow-up, she made progresses regarding social interaction and autonomy, though she maintained an important speech delay. At the age of 3 years, electroencephalography was repeated and did not show abnormalities; at this point she began a progressive withdrawal of phenobarbital, without recurrence of seizures. She only began to speak clearly in simple sentences at the age of four. On her latest evaluation in the Pediatric Neurodevelopment Department, at the age of seven, she revealed a very good memory capacity, she could read simple words and showed a favorable improvement in verbal and non-verbal interactions. Subjectively, she appears to have a normal cognitive function. She currently attends the first grade of elementary school, and she has interest and good performance in Mathematics according to her teacher.
Additional evaluation included array comparative genomic hybridization (aCGH) and Angelman syndrome methylation analysis which were normal. A clinical exome sequencing (CES) was performed, and a heterozygous variant of uncertain significance was identified in the ANK2 gene (NM_001148.5): c.3412C > T p.(Arg1138Ter) (Fig. 1A). The genetic variant was then searched in her parents and was negative in both, suggesting a de novo variant (Fig. 1B).
The child was submitted to a formal cardiac evaluation, ruling out cardiovascular abnormalities.
