Clinical and Genetic Characteristics of Chinese Children With GLUT1 Deficiency Syndrome: Case Report and Literature Review

Abstract

Objective: GLUT1 deficiency syndrome (GLUT1-DS) is a rare, treatable neurometabolic disorder. However, its diagnosis may be challenging due to the various and evolving phenotypes. Here we report the first Chinese familial cases with genetically confirmed GLUT1-DS and analyze the characteristics of Chinese children with GLUT1-DS from clinical, laboratory, and genetic aspects.Methods: We reported a Chinese family with three members affected with GLUT1-DS and searched for relevant articles up to September 2020 from PubMed, WOS, CNKI, and WanFang databases. A total of 30 Chinese patients diagnosed with GLUT1-DS (three newly identified patients in one family and 27 previously reported ones) were included and analyzed in this study.Results: The median age of onset of the 30 patients (male: 18, female: 12) was 8.5 months (range, 33 days to 10 years). Epileptic seizures were found in 25 patients, most with generalized tonic–clonic and focal ones. Movement disorders were found in 20 patients—frequently with ataxia and dystonia, developmental delay in 25 patients, and microcephaly only in six patients. The cerebrospinal fluid (CSF) analysis showed decreased CSF glucose (median: 1.63 mmol/L, range: 1.1–2.6 mmol/L) and glucose ratio of CSF to blood (median: 0.340; range: 0.215–0.484). The genetic testing performed in 28 patients revealed 27 cases with pathogenic variations of the SLC2A1 gene, including 10 missense, nine frameshift, three nonsense, three large fragment deletions, and two splice-site mutations. Most patients had a good response to the treatment of ketogenic diet or regular diet with increased frequency. Although three patients in this Chinese family carried the same pathogenic mutation c.73C > T (p.Q25X) in the SLC2A1 gene, their symptoms and responses to treatment were not exactly the same.Conclusion: The clinical manifestations of GLUT1-DS are heterogeneous, even among family members sharing the same mutation. For children with unexplained epileptic seizures, developmental delay, and complex movement disorders, detection of low CSF glucose or SLC2A1 gene mutations is helpful for the diagnosis of GLUT1-DS. Early initiation of ketogenic diet treatment significantly improves the symptoms and prognosis of GLUT1-DS.

One Molecule for Mental Nourishment and More: Glucose Transporter Type 1—Biology and Deficiency Syndrome

“…The predominant manifestations are seizures (that usually begin during the first year of life), after an uneventful fetal and neonatal development (due to immature tight junctions in the BBB that allow paracellular glucose transport) [ 12 ]. Five seizure types were described: generalized tonic or clonic, myoclonic, atypical absence, atonic, and unclassified [ 12 , 23 , 29 , 31 , 32 , 33 , 34 ]. Eye movements, an early warning sign which is sometimes inaugural for Glut1DS, usually disappear after early infancy [ 35 ].…”

“…Nevertheless, apneic episodes or abnormal episodic eye movements simulating opsoclonus may precede the onset of seizures by several months [ 23 , 29 ]. In the non-classical Glut1DS phenotype there are usually no seizures, but intellectual disability, impaired language development and intermittent ataxia are seen, sometimes with associated microcephaly [ 32 , 38 ]. Other common manifestations in the non-classical phenotype of the disease are spasticity, dyspraxia and paroxysmal exercise-induced dyskinesia (PED) with transient involuntary movements such as dystonia, chorea or ballism [ 32 ].…”

“…In the non-classical Glut1DS phenotype there are usually no seizures, but intellectual disability, impaired language development and intermittent ataxia are seen, sometimes with associated microcephaly [ 32 , 38 ]. Other common manifestations in the non-classical phenotype of the disease are spasticity, dyspraxia and paroxysmal exercise-induced dyskinesia (PED) with transient involuntary movements such as dystonia, chorea or ballism [ 32 ]. PED has been found to be an allelic variant of classic Glut1DS [ 12 ].…”

“…Glut1DS is mainly caused by pathogenic variants of the SLC2A1 gene; approximately 90% of patients exhibit a heterozygous de novo mutation, while 10% inherit a deficient gene from their parents (which seems to correlate with a milder phenotype) [ 29 , 32 ]. In most cases, Glut1DS exhibits an autosomal dominant inheritance pattern.…”

“…So far, over 200 types of genetic defects have been described, among which are missense, nonsense, frameshift, and splice-site mutations, and large fragment deletions [ 12 , 32 ]. Of these, missense mutations seem to be associated with a milder phenotype, but no definite genotype–phenotype correlation has been described [ 5 , 45 ].…”