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 die

Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice.

Contains fulltext : 110515.pdf (publisher's version ) (Open Access)Cerebrospinal fluid (CSF) analysis is an important tool in the diagnostic work-up of many neurological disorders, but reference ranges for CSF glucose, CSF/plasma glucose ratio and CSF lactate based on studies with large numbers of CSF samples are not available. Our aim was to define age-specific reference values. In 1993 The Nijmegen Observational CSF Study was started. Results of all CSF samples that were analyzed between 1993 and 2008 at our laboratory were systematically collected and stored in our computerized database. After exclusion of CSF samples with an unknown or elevated erythrocyte count, an elevated leucocyte count, elevated concentrations of bilirubin, free hemoglobin, or total protein 9,036 CSF samples were further studied for CSF glucose (n = 8,871), CSF/plasma glucose ratio (n = 4,516) and CSF lactate values (n = 7,614). CSF glucose, CSF/plasma glucose ratio and CSF lactate were age-, but not sex dependent. Age-specific reference ranges were defined as 5-95(th) percentile ranges. CSF glucose 5(th) percentile values ranged from 1.8 to 2.9 mmol/L and 95(th) percentile values from 3.8 to 5.6 mmol/L. CSF/plasma glucose ratio 5(th) percentile values ranged from 0.41 to 0.53 and 95(th) percentile values from 0.82 to 1.19. CSF lactate 5(th) percentile values ranged from 0.88 to 1.41 mmol/L and 95(th) percentile values from 2.00 to 2.71 mmol/L. Reference ranges for all three parameters were widest in neonates and narrowest in toddlers, with lower and upper limits increasing with age. These reference values allow a reliable interpretation of CSF results in everyday clinical practice. Furthermore, hypoglycemia was associated with an increased CSF/plasma glucose ratio, whereas hyperglycemia did not affect the CSF/plasma glucose ratio

Flow chart of inclusion of CSF samples.

<p>N – number of CSF samples.</p

Age-specific CSF glucose, CSF/plasma glucose ratio and CSF lactate values.

<p>(A) CSF glucose concentration in 8,871 samples. CSF samples with CSF glucose >10.0 mmol/L (n = 4) are not shown; (B) CSF/plasma glucose in 4,516 samples. CSF samples with CSF/plasma glucose >1.5 (n = 5) are not shown; (C) CSF lactate concentration in 7,614 samples. CSF samples with CSF lactate >5000 µmol/L (n = 22) are not shown. Lines indicate 5^th and 95^th percentile values.</p

Summary of literature search for reference ranges of CSF glucose, CSF/plasma glucose ratio and CSF lactate.

<p>N - number of CSF samples included in study; wk(s) – week(s); dys – days; yrs- years; P – percentile.</p

Relation between plasma glucose and CSF glucose.

<p>(A) Relation between plasma glucose and CSF/plasma glucose ratio in 4,508 CSF samples. CSF samples with CSF/plasma glucose ratio >1.5 (n = 5) are not shown. (B) Relation between plasma glucose and CSF glucose in 4,513 CSF samples. The grey areas indicates normoglycemia (plasma glucose >3.0 and <7.8 mmol/L).</p

Age-specific reference values for CSF glucose, CSF/plasma glucose ratio and CSF lactate.

<p>Reference values are based on the 5^th to 95^th percentile values. The subgroups from the original data (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042745#pone.0042745.s001" target="_blank">Tables S1</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042745#pone.0042745.s002" target="_blank">S2</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042745#pone.0042745.s003" target="_blank">S3</a>) were clustered into age groups which are commonly used in daily clinical practice (as used by MeSH, Pubmed).</p>*<p>Reference range after exclusion of CSF samples of patients with an unknown or abnormal plasma glucose (<3.0 mmol/L or >7.8 mmol/L) at the moment of lumbar puncture (only represented if >10% different from to the original value). Numbers between brackets represent values without correction for plasma glucose. ‡Reference range after exclusion of CSF samples with CSF lactate >3000 µmol/L (only represented if >10% different from the original value). Number between brackets represents upper limit without exclusion of CSF samples with CSF lactate >3000 µmol/L.</p

Eye movement disorders in inborn errors of metabolism : A quantitative analysis of 37 patients

Inborn errors of metabolism are genetic disorders that need to be recognized as early as possible because treatment may be available. In late-onset forms, core symptoms are movement disorders, psychiatric symptoms, and cognitive impairment. Eye movement disorders are considered to be frequent too, although specific knowledge is lacking. We describe and analyze eye movements in patients with an inborn error of metabolism, and see whether they can serve as an additional clue in the diagnosis of particularly late-onset inborn errors of metabolism. Demographics, disease characteristics, and treatment data were collected. All patients underwent a standardized videotaped neurological examination and a video-oculography. Videos are included. We included 37 patients with 15 different inborn errors of metabolism, including 18 patients with a late-onset form. With the exception of vertical supranuclear gaze palsy in Niemann-Pick type C and external ophthalmolplegia in Kearns-Sayre syndrome, no relation was found between the type of eye movement disorder and the underlying metabolic disorder. Movement disorders were present in 29 patients (78%), psychiatric symptoms in 14 (38%), and cognitive deficits in 26 patients (70%). In 87% of the patients with late-onset disease, eye movement disorders were combined with one or more of these core symptoms. To conclude, eye movement disorders are present in different types of inborn errors of metabolism, but are often not specific to the underlying disorder. However, the combination of eye movement disorders with movement disorders, psychiatric symptoms, or cognitive deficits can serve as a diagnostic clue for an underlying late-onset inborn error of metabolism