Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder.
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.
Leen
Wilhelmina G
WG
Department of Neurology, Radboud University Nijmegen Medical Centre, 935 Neurology, PO BOX 9101, 6500 HB Nijmegen, The Netherlands. w.leen@neuro.umcn.nl
Klepper
Joerg
J
Verbeek
Marcel M
MM
Leferink
Maike
M
Hofste
Tom
T
van Engelen
Baziel G
BG
Wevers
Ron A
RA
Arthur
Todd
T
Bahi-Buisson
Nadia
N
Ballhausen
Diana
D
Bekhof
Jolita
J
van Bogaert
Patrick
P
Carrilho
Inês
I
Chabrol
Brigitte
B
Champion
Michael P
MP
Coldwell
James
J
Clayton
Peter
P
Donner
Elizabeth
E
Evangeliou
Athanasios
A
Ebinger
Friedrich
F
Farrell
Kevin
K
Forsyth
Rob J
RJ
de Goede
Christian G E L
CG
Gross
Stephanie
S
Grunewald
Stephanie
S
Holthausen
Hans
H
Jayawant
Sandeep
S
Lachlan
Katherine
K
Laugel
Vincent
V
Leppig
Kathy
K
Lim
Ming J
MJ
Mancini
Grazia
G
Marina
Adela Della
AD
Martorell
Loreto
L
McMenamin
Joe
J
Meuwissen
Marije E C
ME
Mundy
Helen
H
Nilsson
Nils O
NO
Panzer
Axel
A
Poll-The
Bwee T
BT
Rauscher
Christian
C
Rouselle
Christophe M R
CM
Sandvig
Inger
I
Scheffner
Thomas
T
Sheridan
Eamonn
E
Simpson
Neil
N
Sykora
Parol
P
Tomlinson
Richard
R
Trounce
John
J
Webb
David
D
Weschke
Bernhard
B
Scheffer
Hans
H
Willemsen
Michél A
MA
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002239:Carbohydrate Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D055423:Diet, Ketogenic; D020820:Dyskinesias / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D005260:Female; D051272:Glucose Transporter Type 1 / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D008297:Male; D009154:Mutation; D010641:Phenotype; D012189:Retrospective Studies; D013577:Syndrome; D055815:Young Adult
D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human