EC Clinical and Medical Case Reports

Background: LNPK-related neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum (NEDEHCC), also known as Lunapark deficiency syndrome, is an extremely rare autosomal recessive disorder caused by pathogenic variants in the LNPK gene. The disorder is characterized by global developmental delay, developmental regression, intellectual disability, refractory epilepsy, and variable neuroimaging abnormalities. Fewer than 20 affected families have been reported worldwide, and the clinical spectrum and optimal management remain poorly defined.

Case Presentation: We report the case of a 5-year-old boy with genetically confirmed LNPK-related neurodevelopmental disorder caused by a homozygous pathogenic LNPK variant who presented with recurrent generalized tonic-clonic and myoclonic seizures triggered by an acute respiratory infection. His medical history was notable for severe global developmental delay, developmental regression following seizure onset, and drug-resistant epilepsy requiring treatment with multiple antiseizure medications. On admission, he was febrile, hypoxemic, and exhibited respiratory distress with radiographic evidence of left-sided pneumonia. Electroencephalography demonstrated persistent epileptiform activity despite multidrug antiseizure therapy. The patient required pediatric intensive care unit admission, continuous intravenous midazolam infusion, optimization of antiseizure medications, respiratory support, enteral nutritional management, and broad-spectrum antimicrobial therapy. Although his respiratory status and inflammatory markers gradually improved, seizure activity remained difficult to control, highlighting the refractory nature of epilepsy associated with LNPK deficiency.

Conclusion: This case illustrates the severe neurological phenotype and therapeutic challenges associated with LNPK-related neurodevelopmental disorder. The combination of profound developmental impairment, developmental regression, and refractory epilepsy complicated by intercurrent infection underscores the importance of early genetic diagnosis, multidisciplinary management, and prompt treatment of seizure-provoking conditions. Reporting additional cases is essential to expand the current understanding of the phenotypic spectrum, natural history, and management strategies for this exceptionally rare disorder.

Keywords: LNPK; Lunapark Deficiency; Neurodevelopmental Disorder; Refractory Epilepsy; Developmental Regression

1. Schwarz DS and Blower MD. “The endoplasmic reticulum: Structure, function and response to cellular signaling”. Cellular and Molecular Life Sciences 1 (2016): 79-94.
2. Perkins HT and Allan V. “Intertwined and finely balanced: Endoplasmic reticulum morphology, dynamics, function, and diseases”. Cells 9 (2021): 2341.
3. Fowler PC., et al. “NeurodegenERation: The central role for ER contacts in neuronal function and axonopathy, lessons from hereditary spastic paraplegias and related diseases”. Frontiers in Neuroscience 13 (2019): 1051.
4. Colla E. “Linking the endoplasmic reticulum to Parkinson’s disease and alpha-synucleinopathy”. Frontiers in Neuroscience 13 (2019): 560.
5. Chen S., et al. “Lunapark stabilizes nascent three-way junctions in the endoplasmic reticulum”. Proceedings of the National Academy of Sciences of the United States of America 2 (2015): 418-423.
6. Shemesh T., et al. “A model for the generation and interconversion of ER morphologies”. Proceedings of the National Academy of Sciences of the United States of America 49 (2014): E5243-E5251.
7. Anggrandariyanny PC., et al. “Lunapark ubiquitinates atlastin-2 for the tubular network formation of the endoplasmic reticulum”. Biochemistry4 (2022): 245-257.
8. Wang S., et al. “Cooperation of the ER-shaping proteins atlastin, lunapark, and reticulons to generate a tubular membrane network”. Elife 5 (2016): e18605.
9. Breuss MW., et al. “Mutations in LNPK, encoding the endoplasmic reticulum junction stabilizer lunapark, cause a recessive neurodevelopmental syndrome”. American Journal of Human Genetics 2 (2018): 296-304.
10. Türkyılmaz A., et al. “Novel LNPK variant causes progressive cerebral atrophy: Expanding the clinical phenotype”. Clinical Genetics 3 (2022): 218-222.
11. Jaganathan K., et al. “Predicting splicing from primary sequence with deep learning”. Cell 3 (2019): 535-548.e24.
12. Pascual B., et al. ““Ears of the lynx” MRI sign is associated with SPG11 and SPG15 hereditary spastic paraplegia”. American Journal of Neuroradiology 1 (2019): 199-203.
13. Murmu RP., et al. “Cellular distribution and subcellular localization of spatacsin and spastizin, two proteins involved in hereditary spastic paraplegia”. Molecular and Cellular Neuroscience 3 (2011): 191-202.
14. Boutry M., et al. “Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis”. Communications Biology 2 (2019): 380.
15. Vantaggiato C., et al. “ZFYVE26/SPASTIZIN and SPG11/SPATACSIN mutations in hereditary spastic paraplegia types AR-SPG15 and AR-SPG11 have different effects on autophagy and endocytosis”. Autophagy1 (2019): 34-57.
16. Ebrahimi-Fakhari D., et al. “Systematic analysis of brain MRI findings in adaptor protein complex 4-associated hereditary spastic paraplegia”. Neurology19 (2021): e1942-e1954.
17. Estrada-Cuzcano A., et al. “Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)”. Brain2 (2017): 287-305.
18. Sáenz-Farret M., et al. “Spastic paraplegia type 7 and movement disorders: Beyond the spastic paraplegia”. Movement Disorders Clinical Practice 4 (2022): 522-529.
19. Agarwal A., et al. ““Ear of the lynx” sign in hereditary spastic paraparesis (HSP) 76”. Movement Disorders Clinical Practice 1 (2022): 120-123.
20. Parashar S and Ferro-Novick S. “Architecture of the endoplasmic reticulum plays a role in proteostasis”. Autophagy4 (2022): 937-938.
21. Bae YJ., et al. “Imaging the substantia nigra in Parkinson disease and other Parkinsonian syndromes”. Radiology 2 (2021): 260-278.
22. Deneubourg C., et al. “The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy”. Autophagy 3 (2022): 496-517.
23. Yamamoto YH and Noda T. “Autophagosome formation in relation to the endoplasmic reticulum”. Journal of Biomedical Science 1 (2020): 97.
24. Ghila L and Gomez M. “The evolutionarily conserved gene LNP-1 is required for synaptic vesicle trafficking and synaptic transmission”. European Journal of Neuroscience 3 (2008): 621-630.
25. Accogli A., et al. “Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies”. Brain Communications5 (2023): fcad222.