Abstract
BackgroundIt has been demonstrated that glucose transporter (GLUT1) deficiency in a mouse model causes a diminished cerebral lipid synthesis. This deficient lipid biosynthesis could contribute to secondary CoQ deficiency. We report here, for the first time an association between GLUT1 and coenzyme Q10 deficiency in a pediatric patient.Case presentationWe report a 15 year-old girl with truncal ataxia, nystagmus, dysarthria and myoclonic epilepsy as the main clinical features. Blood lactate and alanine values were increased, and coenzyme Q10 was deficient both in muscle and fibroblasts. Coenzyme Q10 supplementation was initiated, improving ataxia and nystagmus. Since dysarthria and myoclonic epilepsy persisted, a lumbar puncture was performed at 12 years of age disclosing diminished cerebrospinal glucose concentrations. Diagnosis of GLUT1 deficiency was confirmed by the presence of a de novo heterozygous variant (c.18+2T>G) in the SLC2A1 gene. No mutations were found in coenzyme Q10 biosynthesis related genes. A ketogenic diet was initiated with an excellent clinical outcome. Functional studies in fibroblasts supported the potential pathogenicity of coenzyme Q10 deficiency in GLUT1 mutant cells when compared with controls.ConclusionOur results suggest that coenzyme Q10 deficiency might be a new factor in the pathogenesis of G1D, although this deficiency needs to be confirmed in a larger group of G1D patients as well as in animal models. Although ketogenic diet seems to correct the clinical consequences of CoQ deficiency, adjuvant treatment with CoQ could be trialled in this condition if our findings are confirmed in further G1D patients.
Highlights
It has been demonstrated that glucose transporter (GLUT1) deficiency in a mouse model causes a diminished cerebral lipid synthesis
Ketogenic diet seems to correct the clinical consequences of Coenzyme Q10 (CoQ) deficiency, adjuvant treatment with CoQ could be trialled in this condition if our findings are confirmed in further GLUT1 deficiency syndrome (G1D) patients
CoQ content was increased in GLUT1 mutant fibroblasts after 10 days growth in galactose (Table 1) while it remained unchanged in fibroblasts incubated in glucose media for the same length of time
Summary
It has been demonstrated that glucose transporter (GLUT1) deficiency in a mouse model causes a diminished cerebral lipid synthesis. This deficient lipid biosynthesis could contribute to secondary CoQ deficiency. The main pathophysiological mechanism of the disease is associated with impaired glucose transport across the blood brain barrier and through astrocyte cell membranes that are haploinsufficient in the GLUT1 glucose carrier encoded by the SLC2A1 gene [5,6]. Energy failure has been proven in G1D astrocytes, while tricarboxilyc acid abundance in the brain of G1D mouse model is normal These findings support the complementary or alternative view that additional mechanisms participate in disease pathogenesis, placing new emphasis on G1D as a glial disease [9]. This contention is highlighted by the preliminary therapeutic efficacy of triheptanoin, a dietary supplement with the potential to stimulate cerebral anabolism and energy delivery [10]
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