1 - Department of Pediatrics, Hospital Central do Funchal, Funchal, Madeira, Portugal
2 - Department of Genetics, Hospital de Dona Estefânia, Centro Hospitalar Lisboa Central, Lisbon, Portugal
3 - Department of Neuroradiology, Hospital de Dona Estefânia, Centro Hospitalar Lisboa Central, Lisbon, Portugal
4 - Department of Neuropediatrics, Hospital Central do Funchal, Funchal, Madeira, Portugal
- 15th European Paediatric Neurology Society (EPNS) Congress, 20 a 24 Junho 2023, Praga
Objective: In 2020 Van Bergen et al described a neurodevelopmental disorder with epilepsy, spasticity and brain atrophy (NEDESBA; 618741), in 7 children from 3 unrelated families, associated with a recurrent homozygous splice site variant (c.454+3A>G) in TRAPPC4 gene. TRAPPC4 is one of the core proteins of TRAPP complex, essential for cell survival. We report two sisters with a TRAPPC4-related neurodevelopmental disorder, diagnosed by whole-exome sequencing (WES) after extensive investigation.
Methods: Case report
Results: A family of consanguineous parents, with no known family history of neurological diseases, has two daughters, a 7-year-old and 2-year-old child. The older sister, after an uncomplicated pregnancy and neonatal course, demonstrated acquired microcephaly (-3SD) and developmental delay at 6 months. Bilateral frontotemporal cerebral atrophy and white matter abnormality was reported on brain MRI. Metabolic workup and ophthalmological evaluation had no changes. Array CGH was normal. At 2 years-old with severe developmental delay, with no communicative interaction, microcephaly and spastic quadriparesis, trio-WES revealed no changes. Mitochondrial genome was also requested, with no alterations. At 5 years-old, she had clonic seizures in the left body, with spikes in the right fronto-centro-temporal region on electroencephalogram (EEG), starting antiepileptic treatment with levetiracetam (LVT). Severe and progressive atrophy, white matter abnormality and hypointense thalami/basal ganglia was reported on brain MRI, repeated at age 6. Meanwhile her mother became pregnant and a girl was born, after an uneventful pregnancy. The younger sister started oculogyric crises at 4 months, associated with microcephaly (-4SD), developmental delay, dystonia and psychomotor agitation. EEG reveled centrotemporal and temporal spikes arising independently in the right and left hemispheres. She was put on LVT treatment, but it was necessary to add valproate and clonazepam due to persistent crises. Brain MRI reported moderate cerebral atrophy and marked hypointense thalami/basal ganglia. Re-analysis of WES was performed and showed a pathogenic homozygous variant (c.454+3A>G) in TRAPPC4 gene.
Conclusions: TRAPPC4-related neurodevelopmental disorder is a recent TRAPPopathy that should be considered in children with microcephaly associated with neurodegenerative disease. With this report we intend to draw attention to the emergence of new diagnoses of neurogenetic diseases and the importance of genome re-analysis.
Keywords: TRAPPC4, NEDESBA, TRAPPopathy.