Autosomal dominant HK1-related neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA): An emerging mitochondrial disorder

Abstract

Purpose: Hexokinase 1 (HK1) encodes a ubiquitously expressed hexokinase, which is responsible for the first step of glycolysis, phosphorylation of glucose to glucose-6-phosphate. Both autosomal recessive and dominant variants in this gene have previously been shown to cause human disease, and presently, there are clinical data available for 27 individuals with the monoallelic neurodevelopmental disorder with visual defects and brain anomalies. Delineation of the entire phenotypic spectrum and genotype-phenotype relations will aid in management and counseling decisions.

Methods: We present molecular and clinical data on 22 additional individuals with heterozygous, mostly de novo, variants in HK1. We also reviewed data from the published literature.

Results: The clinical manifestations of neurodevelopmental disorder with visual defects and brain anomalies include varying degrees of intellectual disability/developmental delay, hypotonia, epileptic encephalopathy, visual deficits, a Leigh syndrome spectrum pattern on brain magnetic resonance imaging, and elevated lactate in blood and cerebrospinal fluid, suggesting mitochondrial dysfunction. Based on severity, individuals can be classified into mild, moderate, severe, or lethal forms. In terms of genotype-phenotype correlation, we find that all individuals carrying a missense variant at the threonine 457 residue have severe clinical features.

Conclusion: HK1 should be included in mitochondrial disorder gene sequencing panels.

Keywords: HK1; Hexokinase; Leigh syndrome spectrum; Mitochondrial disorder; NEDVIBA.

Figure 1

Heatmap representation of the clinical findings by variant residues across all reported individuals in this study. Red: present; green: absent; blank: NA or NR. ∗At least 1 of the following: cerebral atrophy, cerebellar atrophy, basal ganglia lesions, and corpus callosum agenesis/hypoplasia with or without accompanying ventriculomegaly. CSF, cerebrospinal fluid; CVI, cortical visual impairment; DD, developmental delay; FTT, failure to thrive; G-tube, gastrostomy tube; ID, intellectual disability; NA, not applicable; NR, not reported; OA, optic atrophy; OSA, obstructive sleep apnea; RP, retinitis pigmentosa.

Figure 2

Distribution of HK1 variants on 2D protein schematic that have been reported in individuals affected with different HK1-related phenotypes. The frequencies of reported variants are provided as a representative lollipop plot with the number of cases provided within respective lollipops. Red: NEDVIBA [AD; OMIM 618547]; maroon: neuropathy, hereditary motor, and sensory, Russe type [AR; OMIM 605285]; blue: nonsyndromic retinitis pigmentosa 79 [AD; OMIM 617460]; green: anemia, congenital, nonspherocytic hemolytic, 5, hexokinase deficient [AR; OMIM 235700]; black: congenital hyperinsulinism [AD; PMID: 36333503]. 2D, 2-dimensional; HK, hexokinase; LoF, loss of function; NEDVIBA, neurodevelopmental disorder with visual defects and brain anomalies; PBD, porin binding domain.

Figure 3

The schematic of hexokinase’s role in the glycolytic pathway (A) and superimposition of the certain NEDVIBA variants on the 3D structure of HK1 (B). HK1 adopts a bi-lobed architecture consisting of 2 globular domains connected by a rigid linker (a-helix). The C-terminal domain has an active site that converts glucose and adenosine triphosphate (ATP) into glucose-6-phosphate (G6P) and adenosine diphosphate (ADP). The N-terminal domain lacks catalytic activity but can bind G6P and serves a regulatory role. The mutations are clustered in 3 regions of the protein corresponding to key sites in the N-terminal domain, the linker region, and the C-terminal domain. p.Gly414, p.Lys418, and p.Ser445 are proximal to the binding site for G6P in the N-terminal domain, suggesting that mutations of these residues may affect the binding or regulatory function of G6P. p.Thr457 is located at the interface between the N-terminal domain and the linker region, which suggests that mutations here could change the structural orientation of the N- and C-terminal domains. p.Arg801, p.Leu804, and p.Ser816 are also clustered together near the linker region, suggesting that variants affecting these residues may disrupt the connection between the N- and C-terminal halves. The p.Ser893 residue is proximal to the binding sites of ATP and glucose, which hints that variants affecting this residue may alter catalytic activity. However, biochemical assays performed on patient cells with the p.(Lys418Glu), p.(Ser445Leu), and p.(Thr457Met) variants have thus far showed that there is no decrease in hexokinase activity. Mapping of the variants onto available atomic models suggests that the variants might induce structural changes to the protein that may have important functional consequences. 3D, 3-dimensional; HK, hexokinase; NEDVIBA, neurodevelopmental disorder with visual defects and brain anomalies.