Objective: To provide unique data on the clinical and genetic spectrum of developmental dyskinetic encephalopathies.

Background: Developmental dyskinetic encephalopathy(DDE) is a recently described clinically and genetically heterogenous disorder characterised by developmental or psychomotor retardation with early onset hyperkinetic movement disorders. With the exciting revelation of genes linked to early-onset epilepsy and paediatric movement disorders, there has been a surge of interest among neurologists in the field of developmental dyskinetic encephalopathies.

Method: We defined DDE as neurodevelopmental disorders marked by early-onset dyskinetic movement disorders, typically occurring without or with infrequent seizures. Twenty-four children who met the defined criteria seen in the Pediatric Neurology and Movement Disorder Clinic were included in this retrospective cohort study(2016-2024). We reviewed the prospectively maintained electronic medical records for clinical, imaging, biochemical, and molecular genetic features. The videos of these patients were also reanalysed. DNA samples were used for targeted next-generation sequencing, or clinical exome or whole exome sequencing and mitochondrial genome sequencing.

Results: There were 24 patients(18 males) and the mean age of onset of movement disorders was 14.3 months (range 3–60). A wide spectrum of genetic variants were found to be associated with DDE. GNAO1 and ADCY5 variants were most common(3 patients each) followed by ATP8A2 and ATP1A3, variants(2 patients each). Other genes were GRID2, GRIA2, GRIA4,GRIN1, KMT2B, GTPBP2, GCDH , NGLY1, ZNF142, TMEM 163, UFSP2, HECW2, and PDHA1 variants. One patient had chromosome 6q deletion. Pathogenic or likely pathogenic variants were seen in 69.5% of patients. Most patients had multiple movement disorders. Chorea and dystonia were the most common movement disorders(17 patients each) followed by ataxia(6 patients), myoclonus(6 patients) and stereotypy(3 patients). Dysmorphism was seen in 10 patients and paroxysmal movement disorders were seen in 3 patients.

Conclusion: The clinical and genetic spectrum of DDE is heterogeneous. The study highlights the importance of looking beyond seizures and cognitive decline in developmental encephalopathies. The recognition of movement disorder types is key in the early diagnosis and management of patients with DDE.

Clinical spectrum of DDE

References: 1. van der Veen S, Tse GTW, Ferretti A, Garone G, Post B, Specchio N, Fung VSC, Trivisano M, Scheffer IE. Movement Disorders in Patients With Genetic Developmental and Epileptic Encephalopathies. Neurology. 2023 Nov 7;101(19):e1884-e1892. doi: 10.1212/WNL.0000000000207808. Epub 2023 Sep 25. Erratum in: Neurology. 2024 Jul 9;103(1):e209596. doi: 10.1212/WNL.0000000000209596. PMID: 37748886; PMCID: PMC10663013.

2. Specchio N, Curatolo P. Developmental and epileptic encephalopathies: what we do and do not know. Brain. 2021 Feb 12;144(1):32-43. doi: 10.1093/brain/awaa371. PMID: 33279965.

3.Papandreou A, Danti FR, Spaull R, Leuzzi V, Mctague A, Kurian MA. The expanding spectrum of movement disorders in genetic epilepsies. Dev Med Child Neurol. 2020 Feb;62(2):178-191. doi: 10.1111/dmcn.14407. Epub 2019 Nov 29. PMID: 31784983

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-genetic-spectrum-of-developmental-dyskinetic-encephalopathy-experience-from-a-tertiary-care-centre/