Lunapark Deficiency Leads to an Autosomal Recessive Neurodevelopmental Phenotype With a Degenerative Course, Epilepsy and Distinct Brain Anomalies Publisher



Accogli A^{1, 2} ; Zaki MS³ ; Alowain M⁴ ; Otaif MY⁵ ; Jackson A^{6, 7} ; Argilli E⁸ ; Chandler KE^{6, 7} ; De Goede CGEL⁹ ; Cora T¹⁰ ; Alvi JR¹¹ ; Eslahi A^{12, 13} ; Asl Mohajeri MS¹² ; Ashtiani S¹⁴ ; Au PYB¹⁴ Show All Authors Show Affiliations
Source: Brain Communications Published:2023

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 nonspecific 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 11 families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified 12 distinct homozygous loss-of-function variants in 16 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. © 2023 The Author(s). Published by Oxford University Press on behalf of Infectious Diseases Society of America.