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Phenotypic Spectrum of Seizure Disorders in MBD5-Associated Neurodevelopmental Disorder
Kenneth A Myers1, Carla Marini1, Gemma L Carvill1
1Research Institute of the McGill University Health Centre (K.M.), Montreal, PQ; Division of Child Neurology (K.M.), Department of Pediatrics, Montreal Children's Hospital, McGill University, Montreal, PQ; Department of Neurology & Neurosurgery (K.M.), Montreal Children's Hospital, McGill University, Montreal, PQ; Child Neurology and Psychiatry (C.M.), Salesi Pediatric Hospital, United Hospitals of Ancona, Ancona, Italy; Division of Genetic Medicine (G.L.C., J.N., H.C.M.), Department of Pediatrics, University of Washington, Seattle, WA; Department of Neurology (A.M.), Great Ormond Street Hospital for Children, London, UK; Developmental Neurosciences Programme (A.M.), UCL Great Ormond Street Institute of Child Health, London, UK; Neurology Network Melbourne (J.P.), Melbourne, Victoria, Australia; Murdoch Children's Research Institute (C.S., I.E.S.), Parkville, Victoria, Australia; Department of Paediatrics and Child Health (T.S.), School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand; Division of Neurology (S.M.), Department of Pediatrics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Neurology Unit and Neurogenetic Laboratories (C.B., A.R., R.G.), Meyer Children's Hospital, Florence, Italy; Department of Clinical Genetics (R.H.S.), Great Ormond Street Hospital, London, UK; Epilepsy Research Centre (I.E.S.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia; Department of Paediatrics (I.E.S.), Royal Children's Hospital, The University of Melbourne, Parkville, Victoria, Australia; and The Florey Institute of Neuroscience and Mental Health (I.E.S.), Heidelberg, Victoria, Australia.
Objective:
To describe the phenotypic spectrum in patients with MBD5-associated neurodevelopmental disorder (MAND) and seizures; features of MAND include intellectual disability, epilepsy, psychiatric features of aggression and hyperactivity, and dysmorphic features including short stature and microcephaly, sleep disturbance, and ataxia.
Methods:
We performed phenotyping on patients with MBD5 deletions, duplications, or point mutations and a history of seizures.
Results:
Twenty-three patients with MAND and seizures were included. Median seizure onset age was 2.9 years (range 3 days-13 years). The most common seizure type was generalized tonic-clonic; focal, atypical absence, tonic, drop attacks, and myoclonic seizures occurred frequently. Seven children had convulsive status epilepticus and 3 nonconvulsive status epilepticus. Fever, viral illnesses, and hot weather provoked seizures. EEG studies in 17/21 patients were abnormal, typically showing slow generalized spike-wave and background slowing. Nine had drug-resistant epilepsy, although 3 eventually became seizure-free. All but one had moderate-to-severe developmental impairment. Epilepsy syndromes included Lennox-Gastaut syndrome, myoclonic-atonic epilepsy, and infantile spasms syndrome. Behavioral problems in 20/23 included aggression, self-injurious behavior, and sleep disturbance.
Conclusions:
MBD5 disruption may be associated with severe early childhood-onset developmental and epileptic encephalopathy. Because neuropsychiatric dysfunction is common and severe, it should be an important focus of clinical management.
Insights
MBD5-associated neurodevelopmental disorder (MAND) often presents with severe early-onset epilepsy and developmental delays. Neuropsychiatric issues like aggression and sleep disturbances are common and require clinical attention.
Area of Science:
- Genetics
- Neuroscience
- Pediatrics
Background:
- MBD5-associated neurodevelopmental disorder (MAND) is a rare genetic condition.
- Phenotypic variability exists among affected individuals.
Purpose of the Study:
- To delineate the phenotypic spectrum of MAND, focusing on patients with seizures.
- To understand the clinical manifestations and management challenges in MAND.
Main Methods:
- Phenotypic characterization of 23 patients with MBD5 genetic alterations (deletions, duplications, point mutations) and a history of seizures.
- Analysis of seizure types, onset, EEG findings, developmental impairment, and behavioral issues.
Main Results:
- Seizures, predominantly generalized tonic-clonic, began in early childhood (median 2.9 years).
- Moderate-to-severe developmental impairment and behavioral problems (aggression, self-injury, sleep disturbance) were prevalent.
- Epilepsy syndromes like Lennox-Gastaut and infantile spasms were observed; some cases showed drug resistance.
Conclusions:
- MBD5 disruption is linked to severe early-onset developmental and epileptic encephalopathy.
- Neuropsychiatric dysfunction is a significant and common feature requiring focused clinical management.
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