Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies

Abstract

LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy, and non-specific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in eleven families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified twelve distinct homozygous loss-of-function variants in sixteen individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor (“ear-of-the-lynx” sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain, and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the “ear of the lynx” sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction.

Clinical and neurogenetic characterisation of autosomal recessive RBL2-associated progressive neurodevelopmental disorder

“…As further confirmation, we also noted in most cases bilateral faint-to-marked signal changes at the level of the forceps minor, in keeping with an "ear-of-the-lynx" sign. This neuroimaging feature has been reported in hereditary spastic paraplegias (SPG7, 11 and 15) 41,42 and other neurodegenerative disorders, including those related to variants in the LNPK, CAPN1, and ATP13A2 [43][44][45] . Indeed, a neurodegenerative component is consistent with our Drosophila data, which suggest that the decreased brain size observed in Rbf hypomorphs is driven by an increase in cell death, most likely arising from cell-cycle defects in neuronal precursors and immature neurons.…”