Authors :
Presenting Author: Senyene Hunter, MD, PhD – University of North Carolina - Chapel Hill
Emma Cardwell, BS – University of North Carolina Hospitals
Stephanie Peck, MS – University of North Carolina Hospitals
Christal Delagrammatikas, PhD – Malan Syndrome Foundation
Muhammad Zafar, MD – Duke University School of Medicine
Sheng Hung, MD – University of North Carolina Hospitals
Ingrid Scheffer, MBBS, PhD, FRACP, FRS – University of Melbourne, Austin Health; The Florey Institute of Neuroscience and Mental Health, University of Melbourne; University of Melbourne, Royal Children’s Hospital; Murdoch Children’s Research Institute
Rationale:
Malan syndrome is a rare intellectual disability-overgrowth syndrome caused by pathogenic variants in NFIX. It is characterized by postnatal overgrowth, intellectual disability, seizures, and dysmorphic features. The epileptology of Malan syndrome has not been delineated. We describe seizure characteristics, electroencephalogram (EEG) findings, and anti-seizure medication (ASM) use in individuals with Malan syndrome to inform diagnosis and management.
Methods:
Clinical features, seizure semiology, response to ASMs, EEG, and brain magnetic resonance imaging (MRI) results were analysed. Where available, medical records and NFIX pathogenic variants were obtained. Interviews with families were conducted where further details were required. Results:
Of the 45 individuals enrolled with Malan syndrome (age 1-29 years, 49% female), 17/45 (38%) had a history of seizures. Medical records were received for 34 patients, of whom 12/34 (32%) had seizures. All individuals had focal to bilateral tonic-clonic seizures with impaired consciousness, with a median age of onset of 5.5 years (range 2-10 years). Seizure semiology included behavioral arrest and staring, followed by unilateral head and eye version and rhythmic hemi-body (facial and extremity) tonic-clonic jerking. Five patients had one episode of convulsive status epilepticus. Seizures were triggered by febrile illness in 6/12 patients (50%); all 12 patients also had afebrile seizures. Four patients had drug-resistant seizures. Oxcarbazepine (4/12), eslicarbazepine (1/12), and levetiracetam (5/12) were the most effective ASMs. EEG was completed for 21 patients. Diffuse background slowing was common 12/21 (57%), and 6/21 (29%) had focal discharges located over the central (1/6), right or left central-parietal (4/6), or occipital-temporal (1/6) regions. MRI findings were non-specific, including a thin corpus callosum in ten patients, optic nerve hypoplasia in nine, and tonsillar ectopia or Chiari malformation in five patients. Focal cortical dysplasia was found in one individual. Most (21/34, 62%) had a history of global developmental delay ranging from mild to severe, with a median age of onset of 7 months (range 1-34 months); four had concern for developmental regression or plateauing. All individuals had intellectual disability, ranging from mild to severe. Dysmorphologies included macrocephaly, prominent forehead, high anterior hairline, elongated face, downward slanting palpebral fissures, prominent chin, long philtrum, and mild malar hypoplasia. Autism spectrum disorder, anxiety, and behavioral dysregulation were common. Conclusions:
One-third of individuals with Malan syndrome have seizures. All had focal-onset seizures, associated with convulsive status epilepticus and drug-resistance in some. ASMs used to treat focal-onset seizures were effective. EEG and MRI abnormalities identified highlight the importance of obtaining these studies in this rare condition.Funding: None.