Mutation in SNAP25 as a novel genetic cause of epilepsy and intellectual disability
The proband is a 15 y old female, delivered at 41 weeks of gestation. Early prenatal ultrasounds showed bilateral choroid plexus cysts in the brain which were no longer observed by 21 weeks of gestation. APGAR scores were 8 and 9 at 1 and 5 min, respectively. Birth weight was appropriate at 3360 g. The newborn physical exam identified hip dysplasia requiring a Pavlik harness for 4 mo.\nDevelopmentally, she was always delayed in reaching milestones. At 6 weeks of age, the proband’s mother was concerned that she was not making eye contact. At 2.5 mo she was unable to lift her head when prone. Generalized hypotonia was noted at 4 mo. She first sat unsupported at 3 y of age. She can now ambulate with assistance, but does so infrequently. She is non-verbal. She gained weight well from 0–5 mo, maintaining her weight between the 50th–75th centiles but dropped to the 5th centile by 8 mo. Head circumference was also maintained at the 50th centile from 0–5 mo but dropped to the 5th centile by 9 mo. There was no history of developmental regression, but rather a severe delay in development from early life. To optimize nutrition and increase her caloric intake, nasogastric feeds were started at 1 y of age followed shortly thereafter with gastrostomy tube placement.\nSeizures began at 5 mo of age with episodes of repetitive blinking, upward eye deviation and impaired awareness, and were later associated with bilateral kicking and arm abduction accompanied by eye deviation to either side. Video EEG monitoring revealed mild generalized slowing, 2–2.5 Hz generalized spike-and-slow wave complexes. Subsequent video EEG studies revealed (1) mild generalized slowing, (2) interictal partial and symptomatic generalized discharges, and (3) ictal partial and generalized seizures with left (95%) or right-sided (~5%) hemiclonic seizures and lateralized frontocentral discharges (~90% left-sided, ~10% right sided) as well as seizures with bilateral motor features at onset, including tonic-clonic seizures, with generalized discharges. She currently averages 3–10 focal clonic seizures per hour, with an average duration of 15 s. Tonic-clonic seizures occur once every two weeks. Her most recent video EEG showed frequent epileptiform discharges but did not comprise more than 30% of her waking or sleep background. Seizures remain refractory to more than eight antiepileptic drugs in up to three drug combinations, as well as a ketogenic diet and intravenous methylprednisolone trials.\nAt 5 y of age, she required bilateral varus rotation osteotomies of the proximal femurs. She required spinal fusion at 11 y of age for scoliosis.\nHer current neurological examination reveals that she is nonverbal, with global developmental delays. She can intermittently follow simple commands and make intermittent, but fleeting eye contact. Eye tracking is impaired. She is microcephalic with diminished oralmotor tone, excessive drooling and spastic quadriparesis.\nThe proband is an only child. There is no family history of birth defects, seizures, intellectual disability or consanguinity.\nBrain MRI at 8 mo showed delayed myelination, but no structural abnormalities. MR spectroscopy showed increased lactate, raising concern for a mitochondrial disorder but given normal cerebrospinal fluid lactate levels it was thought that the MR spectroscopy lactate peaks were secondary to frequent seizure activity.\nMetabolic screening including quantitative plasma amino acids, acylcarnitine profile, carbohydrate deficient transferrin electrophoresis, urine organic acid analysis, and cerebrospinal fluid neurotransmitters, amino acids, lactate and glucose were all normal. Sulfite oxidase testing for molybdenum cofactor deficiency was normal. Muscle biopsy pathology and electron microscopy, and mitochondrial oxidative phosphorylation enzyme activity in muscle were normal. Electromyogram was normal. Karyotype, subtelomeric FISH, and chromosome microarray were normal. Molecular genetic testing for MECP2, CDKL5, Angelman syndrome methylation, ACAT1, FOXG1, Mitochondrial DNA 3243 allele was negative, MERRF testing on muscle, 101 nuclear encoded mitochondrial genes, 53 epilepsy genes, and 64 genes associated with X linked intellectual disabilities were all normal.