TY - JOUR
T1 - Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic HK1 Variants
AU - Wortmann, Saskia B
AU - Feichtinger, Rene G
AU - Abela, Lucia
AU - van Gemert, Loes A
AU - Aubart, Mélodie
AU - Dufeu-Berat, Claire-Marine
AU - Boddaert, Nathalie
AU - de Coo, Rene
AU - Stühn, Lara
AU - Hebbink, Jasmijn
AU - Heinritz, Wolfram
AU - Hildebrandt, Julia
AU - Himmelreich, Nastassja
AU - Korenke, Christoph
AU - Lehman, Anna
AU - Leyland, Thomas
AU - Makowski, Christine
AU - Martinez Marin, Rafael Jenaro
AU - Marzin, Pauline
AU - Mühlhausen, Chris
AU - Rio, Marlène
AU - Rotig, Agnes
AU - Roux, Charles-Joris
AU - Schiff, Manuel
AU - Haack, Tobias B
AU - Syrbe, Steffen
AU - Zylicz, Stas A
AU - Thiel, Christian
AU - Veiga da Cunha, Maria
AU - van Schaftingen, Emile
AU - Wagner, Matias
AU - Mayr, Johannes A
AU - Wevers, Ron A
AU - Boltshauser, Eugen
AU - Willemsen, Michel A
PY - 2024/4/5
Y1 - 2024/4/5
N2 - BACKGROUND AND OBJECTIVES: Hexokinase 1 (encoded by ) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals. METHODS: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic variants and an NDD phenotype. RESULTS: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile. DISCUSSION: Genotype-phenotype correlations appear to exist for variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.
AB - BACKGROUND AND OBJECTIVES: Hexokinase 1 (encoded by ) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals. METHODS: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic variants and an NDD phenotype. RESULTS: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile. DISCUSSION: Genotype-phenotype correlations appear to exist for variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.
U2 - 10.1212/NXG.0000000000200146
DO - 10.1212/NXG.0000000000200146
M3 - Article
SN - 2376-7839
VL - 10
JO - Neurology. Genetics
JF - Neurology. Genetics
IS - 2
M1 - 200146
ER -