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Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder

Wilhelmina G. Leen , Joerg Klepper , Marcel M. Verbeek , Maike Leferink , Tom Hofste , Baziel G. van Engelen , Ron A. Wevers , Todd Arthur , Nadia Bahi-Buisson , Diana Ballhausen , Jolita Bekhof , Patrick van Bogaert , Inês Carrilho , Brigitte Chabrol , Michael P. Champion , James Coldwell , Peter Clayton , Elizabeth Donner , Athanasios Evangeliou , Friedrich Ebinger , Kevin Farrell , Rob J. Forsyth , Christian G. E. L. de Goede , Stephanie Gross , Stephanie Grunewald , Hans Holthausen , Sandeep Jayawant , Katherine Lachlan , Vincent Laugel , Kathy Leppig , Ming J. Lim , Grazia Mancini , Adela Della Marina , Loreto Martorell , Joe McMenamin , Marije E. C. Meuwissen , Helen Mundy , Nils O. Nilsson , Axel Panzer , Bwee T. Poll-The , Christian Rauscher , Christophe M. R. Rouselle , Inger Sandvig , Thomas Scheffner , Eamonn Sheridan , Neil Simpson , Parol Sykora , Richard Tomlinson , John Trounce , David Webb , Bernhard Weschke , Hans Scheffer , Michél A. Willemsen
DOI: http://dx.doi.org/10.1093/brain/awp336 655-670 First published online: 3 February 2010

Summary

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004–2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month–16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9–2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19–0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet.

  • GLUT1 deficiency syndrome
  • SLC2A1 gene
  • phenotype
  • cerebrospinal fluid
  • ketogenic diet

Introduction

Glucose transporter-1 (GLUT1) deficiency syndrome (OMIM #606777) is an autosomal dominant haplo-insufficiency disorder, leading to a reduced glucose transport into the brain (Seidner et al., 1998). GLUT1 is highly expressed in the endothelial cells of erythrocytes and the blood-brain barrier and is exclusively responsible for glucose transport into the brain (Vannucci et al., 1997; Barros et al., 2007). GLUT1 deficiency syndrome was first described in 1991 by De Vivo et al. (1991). The classic patient with GLUT1 deficiency syndrome presents with infantile drug-resistant seizures, mild to severe developmental delay and an acquired microcephaly in up to 50% of the cases. Hypotonia, spasticity, ataxia and dystonia are elements of a complex movement disorder (Klepper and Leiendecker, 2007). In recent years, however, is has become apparent that the clinical spectrum of GLUT1 deficiency syndrome is much broader (Brockmann, 2009). Patients with a non-classical phenotype featuring developmental delay and movement disorders without epilepsy have been described (Overweg-Plandsoen et al., 2003; Hennecke et al., 2005; Friedman et al., 2006; Klepper et al., 2007), as well as familial and sporadic paroxysmal exercise induced dyskinesia with or without epilepsy (Suls et al., 2008; Weber et al., 2008; Schneider et al., 2009).

When GLUT1 deficiency syndrome is suspected on clinical grounds, a lumbar puncture in the fasting state should be performed. GLUT1 deficiency syndrome is characterized by a low glucose concentration in the cerebrospinal fluid (hypoglycorrhachia) in the absence of hypoglycaemia, in combination with a low to normal lactate in the cerebrospinal fluid (Klepper et al., 1999b; Klepper and Voit, 2002). It is important to recognize GLUT1 deficiency syndrome, since the disorder can be treated with a ketogenic diet. Ketone bodies use another transporter to enter the central nervous system and thus can supply the brain with an alternative fuel.

In most patients the ketogenic diet markedly reduces the frequency of seizures (Klepper et al., 2005) and the severity of the movement disorder (Brockmann, 2009). Behaviour and alertness also frequently improve (Klepper et al., 2005, 2007; Joshi et al., 2008).

For the diagnosis of GLUT1 deficiency syndrome, GLUT1 western blot analysis in erythrocyte membranes and glucose uptake into erythrocytes can be applied to determine GLUT1 function. Negative western blots or erythrocyte uptake studies, however, do not rule out the diagnosis (Klepper et al., 1999a). GLUT1 deficiency syndrome can be confirmed by mutation analysis of the SLC2A1 gene. The SLC2A1 gene, mapped to the short arm of chromosome 1 (1p35-31.3) (Shows et al., 1987), is a relatively small gene and consists of ten exons, spanning 2842 base pairs encoding 493 amino acids (Fukumoto et al., 1988).

The structure and function of the GLUT1 protein has been intensively investigated (Hruz and Mueckler, 2001). The amino-acid sequence of the GLUT1 protein is highly conserved, with 97–98% identity between the human, rat, rabbit, mouse and pig sequences, which implies that all domains of this protein are functionally important (Baldwin, 1993). GLUT1 has 12 transmembrane alpha-helices (Mueckler et al., 1985), separated by a large intracellular loop between helices 6 and 7. A 3D model for GLUT1 has been proposed, predicting a central aqueous channel communicating the extracellular and intracellular compartments, with many residues crucial for glucose transport located around this central channel (Mueckler and Makepeace, 2009).

Since the first description of GLUT1 deficiency syndrome and the elucidation of its genetic cause, a wide spectrum of around 60 different mutations in the SLC2A1 gene has been described in approximately 100 patients (Wang et al., 2005; Klepper and Leiendecker, 2007), including large-scale deletions, missense, nonsense, frame shift and splice-site mutations. All mutations either lead to absence or loss of function of one of the SLC2A1 alleles. Several hot spots for recurrent mutations have been identified (Asn34, Gly91, Ser113, Arg126, Arg153, Arg264, Thr295, Arg333) (Klepper and Leiendecker, 2007). Thus far, correlations between phenotype and genotype remained elusive (Wang et al., 2005; Brockmann, 2009). Here we report on the genetic, biochemical and clinical characteristics of 57 newly diagnosed patients with GLUT1 deficiency syndrome.

Materials and methods

Patients

From January 2004 to July 2008 the DNA Diagnostics Laboratory (Department of Human Genetics of the Radboud University Nijmegen Medical Centre, The Netherlands) received 132 requests for mutational analysis of the SLC2A1 gene in patients suspected to have GLUT1 deficiency syndrome from all over the world (excluding the requests for carrier testing in parents and other family members of affected patients). In 54 patients (41%) suspicion of GLUT1 deficiency syndrome was confirmed by the identification of a pathogenic mutation in the SLC2A1 gene. Additionally, we identified a mutation in the SLC2A1 gene in three clinically affected family members, bringing the total number of patients with GLUT1 deficiency syndrome confirmed by mutation analysis to 57. Clinical data were retrospectively collected from referring physicians by means of a written, detailed questionnaire. Results were reviewed against the background of the existing literature on SLC2A1 gene mutations and associated phenotypes.

Mutation analysis

Genomic DNA was extracted from blood samples by standard procedures. Automated Sanger sequencing was performed to study the entire coding sequence including at least 20 base pairs of intronic sequence flanking each exon of the SLC2A1 gene. Polymerase chain reaction (PCR) amplification of all 10 exons of the SLC2A1 gene was performed using Fast PCR Master Mix (Applied Biosystems, Foster City, California, USA). Primer sequences are available upon request. Sequencing reactions were carried out using BigDye V. 3.1 (Applied Biosystems) and analysed on an ABI 3730 capillary sequencer (Applied Biosystems). Sequences were compared to the wild-type sequence as submitted to Genbank (Genbank Accession Number NM_006516). All previously unreported mutations were verified in a panel of at least 100 control alleles. The reference sequence was used in which the A of the ATG start-codon is designated position 1. Amino-acid residues were numbered from the first methionine residue; according to the protein accession number NP_006507.

Single or multiple exon deletions or duplications of the SLC2A1 gene using multiplex ligation-dependent probe amplification were analysed in all patients. Multiplex ligation-dependent probe amplification is a technique for measuring allele dosage and identifies the target sequence by hybridization of two adjacent complementary probes (Schouten et al., 2002). Multiplex ligation-dependent probe amplification was carried out using the SALSA MLPA kit P138 SLC2A1 (MRC Holland, Amsterdam, The Netherlands) according to the manufacturer’s instructions. A visual comparison of the peak profiles was made to identify copy number changes. Heterozygous deletions of probe recognition sequences should give 35–50% reduced relative peak area of the amplification product of that probe.

Statistical analysis

Statistical analyses were performed using Statistical Package for the Social Sciences version 16.0 (SPSS INC, Chicago, IL, USA). Mean differences in CSF parameters between patients with a different genotype or phenotype were assessed by means of analysis of variance (one-way ANOVA) using planned contrasts for group comparisons. Correlation between phenotype and genotype was tested using the Pearson Chi square test (two-sided testing for a significance level of P ≤ 0.05).

Results

Molecular data

Out of 57 patients, 6 (11%) were identified with a multiple exon deletion of the SLC2A1 gene detected by multiplex ligation-dependent probe amplification. In 51 patients a pathogenic mutation in the SLC2A1 gene was identified by DNA sequence analysis (Table 1). We identified 37 different novel pathogenic mutations, including 13 missense, 5 nonsense, 13 frame shift, 4 splice and 2 translation initiation mutations. We identified two different de novo mutations in amino-acid residue 1 (c.1A > G and c.3G > A). Since the mutations were located in the transcription codon of the SLC2A1 gene, transcription was not initiated, which is consistent with haplo-insufficiency. We identified 17 different missense mutations in the SLC2A1 gene, 13 of which were novel. Eleven novel missense mutations were identified in patients with the classical phenotype of GLUT1 deficiency syndrome of epilepsy and mental retardation in combination with movement disorders (p.Asn34Tyr, p.Met96Val, p.Ala155Val, p.Arg212Cis, p.Arg212His, p.Arg223Trp, p.Glu329Gln, p.Arg333Gln, p.Gly382Asp, p.Ala405Asp, p.Pro485Leu). The novel missense mutation p.Arg153His was identified in Patient 48 with the non-classical phenotype of mild mental retardation with continuous ataxia and paroxysmal dystonia and choreoathetosis. CSF in this patient showed a characteristic pattern of low CSF glucose (1.8 mmol/l) in combination with low CSF : blood glucose ratio (0.38) and low CSF lactate (1.0 mmol/l). The novel missense mutation p.Val303Leu was identified in Patient 57. This patient was lost as follow-up and clinical data were unavailable. DNA of the parents of this patient was not investigated.

View this table:
Table 1

Mutations in the SLC2A1 gene in 51 novel GLUT1 deficiency syndrome patients

ExonNucleotideAmino acidLocationType of mutationPatient numberPhenotypeReferencesa
1c.1A > Gp.Met1?Transcription codonB42B
1c.3G > Ap.Met1?Transcription codonB26A
Intron 1c.18 + 1G > CB24A
Intron 1c.18 + 1G > AB23, 55A, minimalWang et al., 2000
2c.32_33delHelix 1B21A
2c.100A > Tp.Asn34TyrExtracellular loop 1–2A1A
Intron 2c.115-1G > AB17A
3c.124G > Tp.Glu42XExtracellular loop 1–2B46B
3c.160G > Tp.Glu54XExtracellular loop 1–2B54C
3c.170dupExtracellular loop 1–2B18A
4c.277C > Tp.Arg93TrpCytoplasmic loop 2–3A50CJoshi et al., 2008
4c.286A > Gp.Met96ValHelix 3A3A
4c.305_308delHelix 3B43B
4c.338_352delinsTTGAGHelix 3B13A
4c.354_355insTExtracellular loop 3–4B14A
4c.376C > Tp.Arg126CysHelix 4A6, 11, 47, 49A, A, C, CPascual et al., 2002; Zorzi et al., 2008
4c.388G > Ap.Gly130SerHelix 4A5AWang et al., 2005
4c.458G > Ap.Arg153HisCytoplasmic loop 4–5A48C
4c.464C > Tp.Ala155ValHelix 5A39, 37B, B
4c.481C > Tp.Gln161XHelix 5B28A
4c.505_507delHelix 5B20APascual et al.2002; Wang et al., 2005
5c.634C > Tp.Arg212CysCytoplasmic loop 6–7A8A
5c.635G > Ap.Arg212HisCytoplasmic loop 6–7A7A
5c.667C > Tp.Arg223TrpCytoplasmic loop 6–7A40B
6c.715_716insCCytoplasmic loop 6–7B25A
6c.727G > Tp.Glu243XCytoplasmic loop 6–7B16A
6c.737_741delCytoplasmic loop 6–7B56NA
6c.746del; 746-747ins9Cytoplasmic loop 6–7B15, 45A, B
6c.790dupCytoplasmic loop 6–7B19A
6c.798_799insCCytoplasmic loop 6–7B12A
6c.844C > Tp.Gln282XHelix 7B29A
Intron 6c.864-1G > CB52C
7c.884C > Tp.Thr295MetExtracellular loop 7–8A9AWang et al., 2005; Fuji et al., 2008
7c.907G > Tp.Val303LeuExtracellular loop 7–8A57NA
7c.966_971delinsTHelix 8B51C
8c.985G > Cp.Glu329GlnCytoplasmic loop 8–9A4A
8c.988C > Tp.Arg330XCytoplasmic loop 8–9B30, 44A, BWang et al., 2000; Ito et al., 2008
8c.998G > Ap.Arg333GlnCytoplasmic loop 8–9A38B
9c.1100dupExtracellular loop 9–10B53C
9c.1145G > Ap.Gly382AspHelix 10A2A
9c.1214C > Ap.Ala405AspHelix 11A41B
Intron 9c.1279-1G > CB22A
10c.1346_1359delHelix 12B27A
10c.1454C > Tp.Pro485LeuCytoplasmic tailA10A
  • Type of mutation: A = missense mutation, B = nonsense, frame shift, splice site, or translation initiation mutation. Six patients with a multiple exon deletion of the SLC2A1 gene (deletion of exon 2–10 in Patient 34 and deletion of exon 1–10 in Patients 31, 32, 33, 35 and 36) are not represented in the table. Phenotype: A = early-onset classical phenotype; B = late-onset classical phenotype; C = non-classical phenotype; NA = data not available.

  • a: Patients with the same mutation described previously in the literature.

All previously unreported mutations were verified in a panel of at least 100 control alleles. Mutations were not mentioned as non-pathogenic polymorphism in the Single Nucleotide Polymorphism database. Two mutation prediction programs were used to predict the pathogenicity of mutations [PolyPhen (Polymorphism Phenotyping) and SIFT (Sorting Intolerant from Tolerant)]. The mutations that we identified and all mutations in the SLC2A1 gene that have been described previously are represented in Fig. 1 (Klepper et al., 2007; Klepper and Leiendecker, 2007; Ito et al., 2008; Joshi et al., 2008; Roulet-Perez et al., 2008; Suls et al., 2008; Takahashi et al., 2008; Ticus et al., 2008; Weber et al., 2008; Zorzi et al., 2008; Bertsche et al., 2009; Slaughter et al., 2009).

Figure 1

Distribution of 100 different pathogenic mutations in the SLC2A1 gene in 162 patients with GLUT1 deficiency syndrome that were identified by us or have previously been described in literature. Six patients that we identified with a heterozygous multiple exon deletion and five patients that were described previously with haplo-insufficiency of the SLC2A1 gene are not represented. The black vertical line represents the GLUT1 gene with boxes indicating the exons. The left hand diagram shows missense and nonsense mutations. Amino-acid residues at the intron/exon boundaries are shown. The right hand diagram shows frame shift and splice-site mutations. Nucleotides at the intron–exon boundaries are indicated. Genbank Accession Number NM_006516 was used as the SLC2A1 reference sequence in which the A of the ATG start-codon is designated position 1. Some mutations have been reported in the past with a different reference sequence (in which the A of the ATG start-codon is +180); we have adapted these mutations to the reference sequence as mentioned above. The number between brackets represents total number of patients identified with the mutation. Mutation hot spots are represented in bold. *Novel mutation identified in our patient group. **Novel mutation identified in one of our patients that has previously been reported as a case report. ***Mutation identified in our patient group that has previously been reported in other patients. References of mutations that have been described by others after 2007 are mentioned. All other mutations have been described previously by Klepper and Leiendecker (2007).

Autosomal dominant transmission

We identified four families with autosomal dominant transmission of GLUT1 deficiency syndrome. Patient 11 (Table 2), the mother of Patient 49 (Table 4) was diagnosed with GLUT1 deficiency syndrome after diagnosis was made in her daughter. Whereas her daughter had a non-classical phenotype, with mild mental retardation with continuous ataxia with paroxysmal worsening, the mother had the early-onset classical phenotype of epilepsy with mild mental retardation and paroxysmal ataxia.

View this table:
Table 2

Characteristics of 36 novel GLUT1 deficiency syndrome patients with the early-onset classical phenotype

Patient characteristicsType of mutationBiochemical dataClinical dataEffect of ketogenic diet on
PatientSex; ageCSF : blood glucose ratioCSF blood glucoseCSF lactateAge at diagnosisSeizures; onset/ frequencyMicrocephalyMental retardationHypotoniaPyramidal signsMovement disorder
yearsmmol/lmmol/lyearsmonthsAtaxiaDystoniaChoreaSeizuresMovement disorderCognition
1F; 1.4A0.281.30.60.21/WMild++N/A
2M; 4A0.301.71.40.44/M+Sev++P+/–
3F; 8A0.312.01.0715/DMild+/–N/A+
4F; 3A<0.4NANANA6/NANANANANANANANANANANA
5F; 19A0.402.00.9164/W+Mild‡PP++/–
6M; 21A0.412.11.1173/DMod+C+/–+
7aF; 12A0.421.91.193/DMild+N/A+
8F; 19A0.432.11.21715/DNAMild‡NANANANA
9M; 12A0.432.41.393/MMild‡+C/PP+/–+
10aF; 11A0.452.0NA912/DMild+/–N/A+
11F; 34ANANANA336/WNAMildP+/–(MA)
12M; 4B0.191.10.90.42/DMild++N/A+
13M; 7B0.251.30.643/DMod‡+PCC+
14F; 5B0.281.30.90.81/W+Mild+C++
15M; 16B0.291.81.11423/M+Sev‡+C/P000
16F; 3B0.301.41.022/D+Mod‡C++/–+
17M; 17B0.311.3NA152/MNASev‡C000
18M; 12B0.312.2NA1113/D+Mod++000
19F; 16B0.321.40.7143/DMod+C+/–
20M; 7B0.361.6NA43/WMod+C+
21M; 7B0.361.71.249/WMod‡+CC/P++/–+
22aM; 5B0.371.9NA24/D+Mod‡+PP++/–
23M; 5B0.381.7NA43/NAMild+N/A
24F; 19B0.381.80.7146/DSevNA+C+/–; S–; S–; S
25M; 8B0.392.00.748/S+Mod++CC++/–+
26M; 12B0.381.81.0711/NA+Mod++/–+
27M; 24B0.402.11.5204/DMild‡+P++/–
28M; 14BNANANANA6/S+Mod++CC000
29F; 10BNA1.51.1814/SMod‡++CC+/–(MA)+/–
30F; 13BNANANA112/D+Sev+C+
31F; 6C0.200.9NA5+MildC++
32F; 2C0.291.30.90.73/DMod‡++N/A+
33F; 7C0.321.60.966/S+Mod++PP+; S+; S–; S
34M; 3C0.351.91.51.72/W+Mod‡++C++/–+
35F; 9C0.371.61.5512/WSev++C++/–
36M; 10C0.391.6NA75/D+Mod+C/PP+
Total (mean; range)M 50% F 50% 10.7; 1.4–34A 31% B 53% C 17%0.36; 0.19–0.451.7; 0.9–2.41.0; 0.6–1.58.3; 0.2–336.3; 1–23+ 39% − 50% NA 11%Mild 36% Mod 44% Sev 17% NA 3%+ 50% − 42% NA 8%+ 39% − 58% NA 3%C 36% P 17% C/P 8% + 3% − 33% NA 3%C 17% P 14% C/P 3% − 64% NA 3%C 3% P 3% C/P 0% − 92% NA 3%
+ 53%+ 3%+ 42%
+/– 22%+/– 31%− 42%
− 8%− 31%0 11%
0 11%0 11%NA 6%
S 6%S 6%
NA 6%NA 6%
N/A 19%
  • Three patients are not described in the table: Patient 55 had a minimal phenotype; clinical data from Patients 56 and 57 were unavailable.

  • Sex: M = male; F = female. Type of mutation: A = missense mutation; B = nonsense, frame shift, splice site, or translation initiation mutation; C = multiple exon deletion. Seizure frequency: D = daily; W = weekly; M = monthly; S = sporadic. Microcephaly: + = more than two standard deviations below the mean; − = within two standard deviations from the mean. Mental retardation: mild = IQ 50–70; mod = moderate (IQ 35–49); sev = severe (IQ 20–34); ‡ = IQ test was not performed, the severity of mental retardation was based on school level and/or clinical impression of the treating physician. Movement disorder: C = continue; P = paroxysmal; C/P = continue with paroxysmal worsening. Effect of ketogenic diet on (i) seizures: + = seizure free; +/– = reduction of seizures; – = no reduction of seizures; (ii) movement disorder: + = total disappearance of movement disorder; +/– = reduction of frequency and/or severity of movement disorder; – = no effect on movement disorder; (iii) cognition: + = subjective improvement of alertness and behaviour; – = no change in alertness or behaviour; S = ketogenic diet was stopped/patient was non-compliant; 0 = ketogenic diet was not started; MA = modified Atkins diet. NA = data not available; N/A = not applicable.

  • a: Four patients were previously published as a case report: 7 (Roulet-Perez et al., 2008); 10 (Slaughter et al., 2009); 22 (Ticus et al., 2008); 54 (Klepper et al., 2007).

View this table:
Table 3

Characteristics of 10 novel GLUT1 deficiency syndrome patients with the late-onset classical phenotype

Graphic
  • Three patients are not described in the table: Patient 55 had a minimal phenotype; clinical data of Patients 56 and 57 were unavailable. Abbreviations same as in Table 2 footnote.

View this table:
Table 4

Characteristics of 8 novel GLUT1 deficiency syndrome patients with the non-classical phenotype

Patient characteristicsType of mutationBiochemical dataClinical dataEffect of ketogenic diet on
PatientSex; ageCSF : blood glucose ratioCSF blood glucoseCSF lactateAge at diagnosisSeizures; onset/ frequencyMicrocephalyMental retardationHypotoniaPyramidal signsMovement disorder
Yearsmmol/lmmol/lyearsmonthsAtaxiaDystoniaChoreaSeizuresMovement disorderCognition
47M; 5A0.351.61.14Mild+CPN/A+/–
48M; 7A0.381.81.06Mild‡+CPPN/ASS
49F; 13A0.432.00.711+Mild‡+C/PN/A+/–
50bM; 10A0.472.01.09Sev+CN/A00
51F; 7B0.371.80.94Sev‡+++N/A+/–
52M;10B0.381.8NA9+Mod+CCN/A+/–
53F; 3B0.401.5NA1.7+Mod++PN/A+
54aM; 7B0.46NANA3+Mild++CN/A+/–+
Total (mean; range)M 63% F 38% 7.8; 3–13A 50% B 50% C 0%0.41; 0.35–0.471.8; 1.5–2.00.9; 0.7–1.16.0; 1.7–11– 100%+ 50% − 50%Mild 50% Mod 25% Sev 25%+ 63% − 38%+ 63% − 38%C 50% P 0% C/P 13% + 13% − 25%C 13% P 38% C/P 0% − 50%C 13% P 13% C/P 0% + 13% − 63%
N/A+ 0%+ 25%
100%+/– 63%− 50%
− 13%0 13%
0 13% S 13%S 13%
  • Three patients are not described in the table: Patient 55 had a minimal phenotype; clinical data from Patients 56 and 57 were unavailable. Abbreviations same as in Table 2 footnote.

  • a: Four patients were previously published as a case report: 7 (Roulet-Perez et al., 2008); 10 (Slaughter et al., 2009); 22 (Ticus et al., 2008); 54 (Klepper et al., 2007).

  • b: Patient also carried a mutation in the RYR2-gene (Phe2307Leu in exon 45) with the phenotype of catecholaminergic polymorphic ventricular tachycardia.

Patient 55, the mother of Patient 23 (Table 2), was diagnosed with GLUT1 deficiency syndrome after diagnosis was made in her son. The son had the early-onset classical phenotype with a mild mental retardation without movement disorders, whereas the mother had a minimal phenotype with a normal psychomotor development and ‘clumsiness’ after prolonged fasting.

The missense mutation Arg93Trp was also identified in the brother and mother of Patient 50 (Table 4). Patient 50 had a non-classical phenotype of severe mental retardation with chorea. The brother had epilepsy and a mild mental retardation. The mother had epilepsy and a normal intelligence within the lower range (based on the clinical impression of the treating physician).

In one other family the mutation in the SLC2A1 gene was most likely transmitted in an autosomal dominant way. A mutation in the SLC2A1 gene was identified in Patient 45 (Table 3) after diagnosis of GLUT1 deficiency syndrome was made in his brother (Patient 15, Table 2). Patient 15 had the early-onset classical phenotype with severe mental retardation, whereas Patient 45 had the late-onset classical phenotype with only mild mental retardation. DNA of their mother was investigated and did not show the mutation. Clinical data and DNA of the father were unavailable.

In all other cases where both parents had been tested (n = 11; 22%) the mutation had occurred as a de novo event.

Biochemical characteristics

The biochemical characteristics of the patients are listed in Tables 2—4. All patients had low CSF glucose concentrations (<2.5 mmol/l). The CSF glucose values (reference range 2.5–3.7 mmol/l) were 0.9–2.4 mmol/l (mean 1.8 mmol/l; SD 0.3). CSF : blood glucose ratios (reference range 0.5–0.8) ranged from 0.19 to 0.52 (mean 0.37; SD 0.07). CSF lactate (reference range 1.3–1.9 mmol/l) ranged from 0.6 to 1.5 mmol/l (mean 1.0 mmol/l; SD 0.2), with a CSF lactate below 1.3 mmol/l in 78% of the patients.

Clinical characteristics

We obtained clinical data of 55 patients (96%). The clinical characteristics are listed in Tables 24. Two patients (56 and 57) were lost to follow-up and clinical data were unavailable. We recognized three different phenotypes. The most frequent, ‘classical’ phenotype (n = 46; 84%) represented patients with refractory epilepsy and developmental delay. Patients generally had an onset of seizures before the age of 2 years (early-onset classical phenotype, n = 36 (65%; Table 2), however we also encountered patients with the onset of seizures later in life (late-onset classical phenotype, n = 10 (18%; Table 3). Seizure semiology was diverse. In the first year of life paroxysmal eye movements, cyanotic spells, complex absences and atonic seizures were observed. In later years, myoclonic seizures and generalized tonic–clonic attacks were seen. Seizure frequency varied from daily to sporadic attacks. Mental retardation ranged from mild (n = 13; 36%) to moderate (n = 16; 44%) or severe (n = 6; 17%) in patients with the early-onset classical phenotype (data on the severity of mental retardation of one patient were unavailable). In patients with the late-onset classical phenotype severity of mental retardation ranged from mild (n = 7; 70%) to moderate (n = 3; 30%). Complex movement disorders (ataxia, dystonia or chorea) were seen in 69% (n = 25) of the patients with the early-onset and in 90% (n = 9) of patients with the late-onset classical phenotype. Movement disorders were either continuous, paroxysmal or continuous with paroxysmal worsening. Data on head growth were available in 39 patients (85%) with the classical phenotype. Microcephaly was seen in 14 out of 32 patients (44%) with the early-onset, and in two out of seven patients (29%) of the patients with the late-onset classical phenotype.

Furthermore, we observed a non-classical phenotype of patients with a mental retardation and movement disorder, but without epilepsy (n = 8; 15%; Table 4). Mental retardation ranged from mild (n = 4; 50%) to moderate (n = 2; 25%) or severe (n = 2; 25%). Ataxia was seen in 75% (n = 6), dystonia in 50% (n = 4), and chorea in 38% (n = 3) of the patients with this non-classical phenotype. Movement disorders were continuous, paroxysmal, or continuous with paroxysmal worsening. Paroxysmal movement disorders were mostly triggered by fasting or exercise. Microcephaly was seen in 50% (n = 4) of the patients with the non-classical phenotype.

Finally, we identified one adult case of GLUT1 deficiency syndrome (Patient 55, the mother of Patient 24) with a normal psychomotor development and only minimal symptoms. She had one seizure when she was 2-years-old and is ‘clumsy’ after prolonged fasting.

Response to the ketogenic diet

A ketogenic diet was started in 37 out of 46 patients (80%) with the classical phenotype. Out of these 37 patients, 24 (62%) became totally seizure free after introduction of the diet and seizure reduction was seen in nine patients (24%). The frequency and/or severity of movement disorders was significantly reduced in 12 out of 29 patients (41%) with the classical phenotype in combination with a movement disorder. In two patients (7%) the movement disorder totally disappeared after introduction of the ketogenic diet. One of these patients (38) had paroxysmal ataxia. The other patient (33) had paroxysmal ataxia and dystonia. The diet, however, was stopped in Patient 33 because of incompliance. The diet was also stopped in two other patients with the classical phenotype, due to non-compliance.

The ketogenic diet was started in seven out of eight patients (88%) with a non-classical phenotype. Reduction of the frequency and/or severity of the movement disorder was seen in five out of seven patients (71%). The diet was stopped with one patient due to incompliance.

Subjective improvement of cognitive function after initiation of the ketogenic diet was seen in 19 out of 37 patients (51%) with a classical phenotype and in two out of seven patients (29%) with the non-classical phenotype.

Relation between genotype and phenotype

We identified specific relations between genotype and phenotype. First, type of mutation was correlated with the severity of mental retardation. Mild mental retardation was seen in 79% (n = 15) of the patients with a missense mutation (‘type A mutation’; Table 24), whereas only 26% (n = 9) of the patients with a nonsense, frame shift, splice site, or translation initiation mutation (‘type B mutation’), or multiple exon deletion (‘type C mutation’) had mild mental retardation (P = 0.000). Second, type of mutation was correlated with the presence of movement disorders. Movement disorders were less frequently seen in patients with type A mutations (63%; n = 12) than in patients with type B or C mutations (88%; n = 30; P = 0.037). Third, all six patients with type C mutations had the early-onset classical phenotype, whereas 38% (n = 18) of the patients with type B mutations had the late-onset or non-classical phenotype (P = 0.075). The non-classical phenotype was seen in both patients with type A (20%; n = 4) and patients with type B mutations (14%; n = 4). Patients with identical mutations were heterogeneous in phenotype and severity of mental retardation.

Relation between genotype and biochemical data

The CSF : blood glucose ratio was lower in patients with type C (0.32; SD 0.07) than in patients with type A mutations (0.40; SD 0.06; P = 0.009) (Fig. 2). Patients with type B mutations also had a lower CSF : blood glucose ratio (0.35; SD 0.06) than patients with type A mutations (0.40; SD 0.06; P = 0.013). The CSF : blood glucose ratio did not differ significantly between patients with type B or type C mutations (P = 0.289). The CSF glucose value was lower in patients with type C (1.48 mmol/l; SD 0.34) than in patients with type A mutations (1.96 mmol/l; SD 0.26; P = 0.001). The CSF glucose value was also lower in patients with type B (1.68 mmol/l; SD 0.30) than in patients with type A mutations (1.96 mmol/l; SD 0.26; P = 0.003). The CSF glucose did not differ significantly between patients with type B or type C mutations (P = 0.150). CSF lactate did not differ significantly between patients with the type A (1.10 mmol/l; SD 0.23), type B (0.97 mmol/l; SD 0.23), or type C mutations (1.20 mmol/l; SD 0.35; P = 0.129).

Figure 2

Correlation between type of mutation and CSF : blood glucose ratio (A); CSF glucose (B); and CSF lactate (C); and the correlation between phenotype and CSF : blood glucose ratio (D); CSF glucose (E); and CSF lactate (F). Reference range: CSF : blood glucose ratio 0.5–0.8; CSF glucose 2.5–3.7 mmol/l; CSF lactate 1.3–1.9 mmol/l. Type of mutation: A = missense mutation; B = nonsense, frame shift, splice site, or translation initiation mutation; C = multiple exon deletion. *P < 0.05.

Relation between phenotype and biochemical data

Patients with the early-onset classical phenotype had a lower CSF : blood glucose ratio (0.35; SD 0.07) than patients with the late-onset classical phenotype (0.41; SD 0.07; P = 0.009) and patients with the non-classical phenotype (0.41; SD 0.044; P = 0.005) (Fig. 2). The CSF glucose value did not differ significantly between patients with the early-onset classical (1.7 mmol/l; SD 0.35), late-onset classical (1.9 mmol/l; SD 0.30), or non-classical phenotype (1.8 mmol/l; SD 0.19; P = 0.145). CSF lactate did not differ significantly between patients with the early-onset classical (1.03 mmol/l; SD 0.27), late-onset classical (1.16 mmol/l; SD 0.18), or non-classical phenotype (0.94 mmol/l; SD; 0.15; P = 0.264).

Discussion

Our data confirm the wide clinical spectrum of GLUT1 deficiency syndrome as recently described (Brockmann, 2009). The absence of epilepsy in patients with GLUT1 deficiency syndrome is considered uncommon and has only been described in a small number of patients (Overweg-Plandsoen et al., 2003; Hennecke et al., 2005; Friedman et al., 2006; Klepper et al., 2007). We have, however, identified a relatively large number of patients in our cohort (n = 8; 15%) with the non-classical phenotype of mental retardation and movement disorders without epilepsy. Another non-classical phenotype of paroxysmal exercise-induced dyskinesia was recently described (Suls et al., 2008; Weber et al., 2008; Schneider et al., 2009). We did not identify patients with the latter phenotype in our study cohort, but we expect that with the increasing awareness of the clinical variety of GLUT1 deficiency syndrome, diagnosis will be made more frequently in patients with a non-classical phenotype.

Recognizing GLUT1 deficiency syndrome is important since it can be treated with a ketogenic diet. The ketogenic diet is a high-fat, low carbohydrate, normocaloric diet which results in permanent ketosis and provides the brain with an alternative fuel (Klepper et al., 2004). It is currently believed that the ketogenic diet should be initiated as soon as possible and should be maintained at least until adolescence (Klepper et al., 2005; Brockmann, 2009). In our study cohort, the ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders significantly in 48% of the patients with the classical phenotype and 71% of the patients with a non-classical phenotype. Effectiveness of the ketogenic diet in a series of drug-resistant epileptic patients with GLUT1 deficiency syndrome has previously been described (Klepper et al., 2005), but improvement of movement disorders in patients with a non-classical phenotype has only been observed in case reports (Friedman et al., 2006; Brockmann, 2009). Our study underlines the importance of initiating a ketogenic diet, not only in patients with epilepsy, but also in patients with movement disorders without epilepsy. Although subjective improvement of cognitive function, behaviour and alertness was reported in a substantial number of our patients, no objective data exist on the effect of the ketogenic diet on cognitive function. Prospective follow-up studies with standardized neurocognitive tests are needed.

The delay in diagnosing GLUT1 deficiency syndrome is considerable. Patients with the classical phenotype were diagnosed at an average of 6.6 years after the onset of seizures (range 1 month–16 years) (Tables 2 and 3). Our study demonstrates that a lumbar puncture provides the diagnostic clue to GLUT1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet. All GLUT1 deficiency syndrome patients in our cohort had a low CSF glucose concentration (<2.5 mmol/l) and all but one patient had a low CSF : blood glucose ratio (<0.50). Differentiation with other causes of a low CSF glucose and low CSF : blood glucose ratio (bacterial, fungal, or protozoal meningitis and subarachnoidal haemorrhage) can be made not only on the clinical symptoms or CSF cultures, but also on CSF lactate concentrations. Neurons can use lactate as an alternative fuel under circumstances of hypoglycaemia. A low CSF lactate in most patients with GLUT1 deficiency syndrome is therefore thought to reflect the glucose shortage in the brain (Wang et al., 2006). CSF lactate was below 1.6 mmol/l in all our patients and below 1.3 mmol/l in 78% of the patients, whereas CSF lactate is elevated (>2.0 mmol/l) in meningitis and subarachnoidal haemorrhage (Cameron et al., 1993). Furthermore, CSF cell count and protein are normal in GLUT1 deficiency syndrome. We therefore advise to perform a lumber puncture in patients with drug-resistant epilepsy and mental retardation, as well as in patients with unexplained movement disorders, especially if movement disorders worsen or occur after fasting or exercise. Patients with paroxysmal exercise-induced dyskinesia due to GLUT1 deficiency syndrome have been observed in the absence of mental retardation, migraine or epilepsy (Schneider et al., 2009). Notably, in patients with GLUT1 deficiency syndrome with this non-classical phenotype of familial exercise-induced dyskinesia the CSF is less sensitive for diagnosing GLUT1 deficiency syndrome, as normal values for CSF : blood glucose ratio (0.47–0.60; mean 0.52) and CSF glucose (1.8–3.6 mmol/l; mean 2.4 mmol/l) can be found (Suls et al., 2008).

Our results demonstrate that GLUT1 deficiency syndrome is caused by (partial) deletion of the SLC2A1 gene in at least 10% of the patients with GLUT1 deficiency syndrome confirmed by DNA analysis. To date, only five GLUT1 deficiency syndrome patients with a large scale deletion have been reported (De Vivo et al., 1991; Seidner et al., 1998; Wang et al., 2000; Vermeer et al., 2007). Perhaps, multiple exon deletions of a SLC2A1 allele are under-diagnosed at the DNA level as a cause of GLUT1 deficiency syndrome. We advise using multiplex ligation-dependent probe amplification in every patient suspected of GLUT1 deficiency syndrome, especially in patients with an early-onset classical phenotype, since all patients identified with a multiple exon deletion had this phenotype. By performing multiplex ligation-dependent probe amplification in combination with Sanger-based automated sequencing we were able to confirm suspicion of the clinical and/or biochemical diagnosis of GLUT1 deficiency syndrome at the DNA level in 42% of all requests for DNA analysis of the SLC2A1 gene. Regulatory sequences of the SLC2A1 gene, e.g. promoter sequences and/or sequences deep in introns are not included in the molecular diagnostic strategy. Possible mutations in these regions thus may not have been uncovered.

We identified 13 novel missense mutations in the SLC2A1 gene. Eleven of these missense mutations were found in patients with the classical phenotype of GLUT1 deficiency syndrome of epilepsy and mental retardation in combination with movement disorders and a characteristic CSF pattern, which would support the presence of a pathogenic GLUT1 allele. Since just a single DNA variant was identified in the coding region in these cases, this strongly suggests the potential pathogenic nature of these mutations. Furthermore, the position of the mutations in the GLUT1 protein indicates the pathogenicity of the individual mutations. A novel missense mutation was identified in exon 2 (p.Asn34Tyr). Asn34 is the first amino acid in the large extracellular loop connecting transmembrane domains 1 and 2 (Hruz and Mueckler, 2001). It is a conserved residue in most of the GLUT subclasses (Joost and Thorens, 2001) and therefore appears to be a crucial residue for glucose transport. Three other patients have previously been reported with a missense mutation at this location (Wang et al., 2000; Overweg-Plandsoen et al., 2003; Klepper et al., 2005). Two of our patients had the novel missense mutation p.Ala155Val. Ala 155 is part of the transmembrane segment 5, which is predicted to be part of the central channel of GLUT1 and is therefore critical for glucose transport (Salas-Burgos et al., 2004). The alanine residue is part of an evolutionary conserved amino-acid stretch (in mouse, rat, dog, chicken, xenopus and fugus). The novel missense mutations p.Arg212His and p.Arg212Cys were identified in the Patients 7 and 8. Arg212 is part of the large cytoplasmic loop between helices 6–7. Another novel missense mutation was located in the cytoplasmic loop between helices 6–7 (p.Arg223Trp). This mutation is considered pathogenic, since it is not documented in the Single Nucleotide Polymorphism database and has not been identified in more than 100 control alleles. The ‘Sorting Intolerant from Tolerant’ (SIFT) program predicts that the protein will not tolerate the amino-acid change. Several other crucial residues have previously been identified in this loop [Arg218 (Klepper et al., 2005), Lys256 (Wang et al., 2000), Ala275 (Weber et al., 2008)]. We identified a novel mutation in exon 8 (p.Glu329Gln). Glu329 is located at the cytoplasmic loop between helices 8–9. Mutation of Glu345 in the cytoplasmic loop between helices 8–9 in GLUT4, which corresponds with Glu329 in GLUT1, has been shown to lock the transporter in an inward-facing confirmation (Schurmann et al., 1997). Another novel missense mutation was found in exon 8 (Arg333Gln). Arg 333 is part of the highly conserved amino-acid motif Arg-X-Gly-Arg-Arg between helix 8–9. The positive charges in the motif form critical local cytoplasmic anchor points involved in determining the membrane topology in GLUT1. These Arg-X-Gly-Arg-Arg motifs are conserved in many of the members of the major facilitator superfamily. Removal of the positive charges in these motifs causes an aberrant flipping of the corresponding cytoplasmic loop into the exoplasmic compartment (Sato and Mueckler, 1999). Two novel missense mutations were detected in exon 9 (p.Gly382Asp and p.Ala405Asp). Gly382 is located in helix 10 and concerns an evolutionary high conserved residue. Transmembrane segment 10 forms a part of the central aqueous channel. Expression of a Gly382Asp mutant in X. laevis oocytes showed abolished glucose transport capacity and reduced GLUT1 expression on the cell membrane (Mueckler and Makepeace, 2002). Ala405 is located in transmembrane segment 11, which is also predicted to be part of the central aqueous channel. Cysteine-scanning mutagenesis of transmembrane segment 11 showed that Ala405 had significantly increased specific activity relative to the cysteine-less protein (Hruz and Mueckler, 2000). Cysteine and alanine are both amino acids with non-polar side chains. Our patient, however, had alanine replaced by aspartic acid, an amino acid with a polar side chain and negative side chain charge, which changes the hydropathy and therefore is likely to disrupt glucose transport across the aqueous central channel. A novel heterozygous mutation was detected in Patient 10 in exon 10 (p.Pro485Leu). The mutation was located in the cytoplasmic carboxyl tail of the GLUT1 protein and was proven to be de novo.

We cannot completely prove the pathogenic nature of two novel missense mutations. Missense mutation p.Arg153His was identified in a patient with a non-classical phenotype of mild mental retardation, continuous ataxia and paroxysmal dystonia and choreoathetosis. The DNA of the parents of this patient was not investigated. The characteristic CSF pattern with low CSF glucose, low CSF : blood glucose ratio and low CSF lactate, however, supports the pathogenicity of this mutation. Furthermore, Arg153 is positioned in the cytoplasmic loop between helix 3 and 4 and is a crucial residue in a conserved domain. Arg153 is one of the known mutation hotspots in GLUT1 deficiency syndrome (Klepper and Leiendecker, 2007). Patient 57 was identified with the novel missense mutation p.Val303Leu. Val303is located in the exofacial loop between helix 7–8. This patient, unfortunately, was lost to follow-up and clinical data were unavailable. The DNA of the parents of the patient was not investigated. The pathogenic nature of this mutation cannot, therefore, be supported.

Autosomal dominant transmission of GLUT1 deficiency syndrome has only been described in a few families with paroxysmal exercise-induced dyskinesia (Suls et al., 2008; Weber et al., 2008) and some families with the classical phenotype of GLUT1 deficiency syndrome (Brockmann et al., 2001; Klepper et al., 2001). We identified autosomal dominant transmission of GLUT1 deficiency syndrome in four families (nine patients). Although this finding confirms that GLUT1 deficiency syndrome is caused by de novo mutations of the SLC2A1 gene in the majority of patients, it emphasizes on the other hand the importance of further clinical and genetic investigation of family members of GLUT1 deficiency syndrome patients.

The genotypic and phenotypic variability among patients with GLUT1 deficiency syndrome is substantial. Our relatively large series of 57 patients with GLUT1 deficiency syndrome allowed, for the first time, an analysis of genotype–phenotype correlations. It has previously been speculated that large-scale deletions, nonsense, frame shift and splice-site mutations result in 50% loss of the GLUT1 protein and are associated with the moderate, classical phenotype of GLUT1 deficiency syndrome. Heterozygous missense mutations with 50–75% residual function are thought to be associated with mild phenotypes. Missense mutations that result in more than 75% residual transport capacity are speculated to be associated with a minimal phenotype with symptoms related to environmental factors, such as fasting or the use of caffeine (Wang et al., 2005). To allow comparison of the effect of different types of mutation on the phenotype, we have clustered mutations that are likely to give a large disruption of glucose transport into brain (nonsense, frame shift, splice site and translation initiation mutations (‘type B mutations’) and multiple exon deletions (‘type C mutations’), and compared them with missense mutations (‘type A mutations’; Table 2–4). Our data confirm that type of mutation is related to the phenotype. Movement disorders were more frequently seen in patients with type B or C mutations, than in patients with type A mutations. Furthermore, type of mutation was related to the severity of mental retardation. Mild retardation was found more often in patients with type A than in patients with type B or C mutations. However, severe mental retardation was found in a few patients with type A mutations and, in contrast, a mild retardation in some patients with a type B or C mutations. Additionally, patients with the same mutation displayed a heterogeneous range of type and severity of phenotype. Even within families with autosomal dominant transmission of GLUT1 deficiency syndrome, phenotypic diversity was significant, which suggests that secondary genes and other proteins may be involved in glucose transport. Another explanation for the phenotypic diversity is a modulating effect of DNA variants regulatory elements of the wild-type GLUT1 allele that may modulate the expression level of the GLUT1 transporter. This phenotypic diversity within families with autosomal transmission of GLUT1 deficiency syndrome has important implications for genetic counselling. It should be emphasized that although a patient has very few symptoms it is possible that a future child with the same mutation will be severely affected. On the other hand, the argument may be reversed in case of a more severely affected patient.

For the first time, genotype could be correlated with CSF parameters (Fig. 2A–C). Patients with type B or C mutations had lower CSF : blood glucose ratios and lower CSF glucose than patients with type A mutations. This suggests that the residual GLUT1 activity in the blood–brain barrier correlates with the CSF : blood glucose ratio as well as the CSF glucose. In addition, the CSF : blood glucose ratio was correlated with phenotype (Fig. 2D–F). The early-onset classical phenotype was correlated with lower CSF : blood glucose ratios than the late-onset classical phenotype and the non-classical phenotype. This suggests that the degree of disruption of glucose transport into the brain is an indicator of the type and severity of clinical symptoms in GLUT1 deficiency syndrome. In the individual patient, however, a very low CSF : blood glucose ratio was not always related to a more severe phenotype. Apparently, the CSF : blood glucose ratio does not (solely) reflect the severity of the symptoms in GLUT1 deficiency syndrome. A possible explanation for a very low CSF : blood glucose ratio in patients with a relatively mild phenotype is the order in which the lumbar and vein puncture have been performed. If blood samples are taken after the lumbar puncture is performed, the blood glucose can be raised due to stress and this will lower the calculated CSF : blood glucose ratio. Furthermore, CSF and blood glucose can fluctuate in the individual patient due to fasting and stress.

In conclusion, GLUT1 deficiency syndrome is a treatable disorder of glucose transport into the brain caused by a variety of mutations in the SLC2A1 gene, which lead to a neurological disorder with large phenotypic diversity, including a substantial number of patients without epilepsy. A lumbar puncture should be performed in every patient suspected of GLUT1 deficiency syndrome, as the simple measurement of CSF glucose is an inexpensive, widely available method to rapidly provide a sensitive marker for selecting patients for mutation analysis of the SLC2A1 gene and early introduction of the ketogenic diet.

Funding

W.G. Leen was supported by The Netherlands Organisation for Scientific Research (NWO; www.nwo.nl).

Footnotes

  • *These authors contributed equally to this work.

  • Abbreviations:
    Abbreviations
    GLUT1
    glucose transporter-1

References

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