Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.

Maintaining protein lipoylation is vital for cell metabolism. The H-protein encoded by GCSH has a dual role in protein lipoylation required for bioenergetic enzymes including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase, and in the one-carbon metabolism through its involvement in glycine cleavage enzyme system, intersecting two vital roles for cell survival. Here, we report six patients with biallelic pathogenic variants in GCSH and a broad clinical spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated phenotype of developmental delay, behavioral problems, limited epilepsy and variable movement problems. The mutational spectrum includes one insertion c.293-2_293-1insT, one deletion c.122_(228 + 1_229-1) del, one duplication of exons 4 and 5, one nonsense variant p.Gln76*and four missense p.His57Arg, p.Pro115Leu and p.Thr148Pro and the previously described p.Met1?. Via functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies, we demonstrate for the first time that most variants identified in our cohort produced a hypomorphic effect on both mitochondrial activities, protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affect primarily one function only. The clinical features of the patients reflect the impact of the GCSH changes on any of the two functions analyzed. Our analysis illustrates the complex interplay of functional and clinical impact when pathogenic variants affect a multifunctional protein involved in two metabolic pathways and emphasizes the value of the functional assays to select the treatment and investigate new personalized options.

Neural correlates of taste perception in congenital olfactory impairment.

Olfaction and gustation contribute both to the appreciation of food flavours. Although acquired loss of smell has profound consequences on the pleasure of eating, food habits and body weight, less is known about the impact of congenital olfactory impairment on gustatory processing. Here we examined taste identification accuracy and its neural correlates using functional magnetic resonance imaging (fMRI) in 12 congenitally olfactory impaired individuals and 8 normosmic controls. Results showed that taste identification was worse in congenitally olfactory impaired compared to control subjects. The fMRI results demonstrated that olfactory impaired individuals had reduced activation in medial orbitofrontal cortex (mOFC) relative to normosmic subjects while tasting. In addition, olfactory performance as measured with the Sniffin' Sticks correlated positively with taste-induced blood-oxygen-level dependent (BOLD) signal increases in bilateral mOFC and anterior insula. Our data provide a neurological underpinning for the reduced taste perception in congenitally olfactory impaired individuals.