Pediatric-Onset Epilepsy and Developmental Epileptic Encephalopathies Followed by Early-Onset Parkinsonism

Abstract

Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10-15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism.

Keywords: developmental and epileptic encephalopathies; early-onset Parkinsonism; epilepsy; genetics.

Figure 1

Excluded neurogenic conditions featuring epilepsy and Parkinsonism in the context of neurodegeneration.

Figure 2

Flow chart depicting article selection process.

Figure 3

Classification and overview of the disorders described in this review. List of abbreviations: AD: autosomal dominant, AR: autosomal recessive, ATP6AP2: ATPase H+ transporting accessory protein 2, CNVs: copy number variations, DE-EE: developmental and epileptic encephalopathies, DNAJC6: DnaJ heat shock protein family (Hsp40) member C6, DS: deletion syndrome, E: epilepsies, FOXG1: forkhead box G1, ID: intellectual disability, IT15: huntingtin, KCND3: Potassium Voltage-Gated Channel Subfamily D Member 3, MECP2: methyl-CpG binding protein 2, NDD neurodevelopmental disorder, NR4A2: Nuclear Receptor Subfamily 4 Group A Member 2, PPP2R5D: Protein Phosphatase 2 Regulatory Subunit B’Delta, RAB39B: Member RAS Oncogene Family, RTT: Rett syndrome, SCN1A: sodium voltage-gated channel alpha subunit 1, STXBP1: syntaxin binding protein 1, SYNJ1: synaptojanin 1, TBC1D24: TBC1 domain family member 24, WDR45: WD repeat domain 45, XLD: X-linked dominant, XLR: X-linked recessive.