A frame-shift deletion in the PURA gene associates with a new clinical finding: Hypoglycorrhachia. Is GLUT1 a new PURA target?

PURA is a DNA/RNA-binding protein known to have an important role as a transcriptional and translational regulator. Mutations in the PURA gene have been documented to cause mainly a neurologic phenotype including hypotonia, epilepsy, development delay and respiratory alterations. We report here a patient with a frame-shift deletion in the PURA gene that apart from the classical PURA deficiency phenotype had marked hypoglycorrhachia, overlapping the clinical findings with a GLUT1 deficiency syndrome. SLC2A1 (GLUT1) mutations were discarded, so we hypothesized that GLUT1 could be downregulated in this PURA deficient scenario. We confirmed reduced GLUT1 expression in the patient's peripheral blood cells compared to controls predicting that this could also be happening in the blood-brain barrier and in this way explain the hypoglycorrhachia. Based on PURA's known functions as a transcriptional and translational regulator, we propose GLUT1 as a new PURA target. Further in vitro and in vivo studies are needed to confirm this and to uncover the underlying molecular mechanisms.

Evaluation of non-coding variation in GLUT1 deficiency.

AIM: Loss-of-function mutations in SLC2A1, encoding glucose transporter-1 (GLUT-1), lead to dysfunction of glucose transport across the blood-brain barrier. Ten percent of cases with hypoglycorrhachia (fasting cerebrospinal fluid [CSF] glucose <2.2mmol/L) do not have mutations. We hypothesized that GLUT1 deficiency could be due to non-coding SLC2A1 variants. METHOD: We performed whole exome sequencing of one proband with a GLUT1 phenotype and hypoglycorrhachia negative for SLC2A1 sequencing and copy number variants. We studied a further 55 patients with different epilepsies and low CSF glucose who did not have exonic mutations or copy number variants. We sequenced non-coding promoter and intronic regions. We performed mRNA studies for the recurrent intronic variant. RESULTS: The proband had a de novo splice site mutation five base pairs from the intron-exon boundary. Three of 55 patients had deep intronic SLC2A1 variants, including a recurrent variant in two. The recurrent variant produced less SLC2A1 mRNA transcript. INTERPRETATION: Fasting CSF glucose levels show an age-dependent correlation, which makes the definition of hypoglycorrhachia challenging. Low CSF glucose levels may be associated with pathogenic SLC2A1 mutations including deep intronic SLC2A1 variants. Extending genetic screening to non-coding regions will enable diagnosis of more patients with GLUT1 deficiency, allowing implementation of the ketogenic diet to improve outcomes.

Cerebrospinal fluid analysis in the workup of GLUT1 deficiency syndrome: a systematic review.

IMPORTANCE: GLUT1 deficiency syndrome is a treatable neurometabolic disorder, characterized by a low concentration of glucose in cerebrospinal fluid (CSF) and a decreased CSF to blood glucose ratio. Reports of patients with apparently normal CSF glucose levels, however, have raised the question whether CSF analysis is a reliable screening tool for GLUT1 deficiency syndrome. OBJECTIVE: To determine the value of CSF analysis in the workup of GLUT1 deficiency syndrome. EVIDENCE REVIEW: PubMed was searched until July 2012 by using the terms glucose transporter 1 (GLUT-1) deficiency syndrome, glucose transporter defect, and SLC2A1-gene. Relevant references mentioned in the articles were also included. The CSF results of all patients with genetically proven GLUT1 deficiency syndrome described in literature were reevaluated. FINDINGS: The levels of glucose in CSF, the CSF to blood glucose ratios, and the levels of lactate in CSF were reported for 147 (94%), 152 (97%), and 73 (46%) of 157 patients, respectively. The CSF glucose levels ranged from 16.2 to 50.5 mg/dL and were at or below the 10th percentile for all 147 patients. The CSF to blood glucose ratios ranged from 0.19 to 0.59 and were at or below the 10th percentile for 139 of 152 patients (91%), but they could be within the normal range as well. The CSF lactate levels ranged from 5.4 to 13.5 mg/dL and were at or below the 10th percentile for 59 of 73 patients (81%). A typical CSF profile for GLUT1 deficiency syndrome, which is defined as a CSF glucose level at or below the 10th percentile, a CSF to blood glucose ratio at or below the 25th percentile, and a CSF lactate level at or below the 10th percentile, was found in only 35 of 4099 CSF samples (0.9%) present in our CSF database of patients who received a diagnosis other than GLUT1 deficiency syndrome. CONCLUSIONS AND RELEVANCE: We conclude that if age-specific reference values are applied, CSF glucose and lactate levels are adequate biomarkers in the diagnostic workup of GLUT1 deficiency syndrome. Future availability of whole-exome sequencing in clinical practice will make the existence of a reliable biomarker for GLUT1 deficiency syndrome even more important, in order to interpret genetic results and, even more importantly, not to miss SLC2A1-negative patients with GLUT1 deficiency syndrome.

Glucose transporter type I deficiency causing mitochondrial dysfunction.

Mitochondrial disorders are varied in their clinical presentation and pathogenesis. Diagnosis is usually made clinically and genetic defects are often not identified. We present a 6-year-old female patient with a diagnosis of a mitochondrial disorder secondary to complex I deficiency with seizures and developmental delay from infancy. Glucose transporter deficiency was suspected after a lumbar puncture showed hypoglycorrhachia. Her disorder was confirmed genetically as a mutation in her solute carrier family 2, facilitated glucose transporter member 1 (SLCA2) gene. Delayed diagnosis led to delayed treatment, and neurologic sequelae may have been prevented by earlier recognition of this disorder.

Glucose transporter type 1 deficiency syndrome with carbohydrate-responsive symptoms but without epilepsy.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is caused by a defect in glucose transport across the blood-brain barrier. The main symptoms are epilepsy, developmental delay, movement disorders, and deceleration of head circumference. A ketogenic diet has been shown to be effective in controlling epilepsy in GLUT1-DS. We report a female child (3 y 4 mo) who presented with delayed psychomotor development and frequent episodes of staggering, impaired vigilance, and vomiting that resolved promptly after food intake. Electroencephalography was normal. The cerebrospinal fluid-blood glucose ratio was 0.42 (normal ≥ 0.45). GLUT1-DS was confirmed by molecular genetic testing, which showed a novel de novo heterozygous mutation in the SLC2A1 gene (c.497_499delTCG, p.VAL166del). Before starting a ketogenic diet, the child's cognitive development was tested using the Snijders-Oomen Non-Verbal Intelligence Test, which revealed a heterogeneous intelligence profile with deficits in her visuomotor skills and spatial awareness. Her motor development was delayed. Three months after introducing a ketogenic diet, she showed marked improvement in speech and motor development, as tested by the Movement Assessment Battery for Children (manual dexterity 16th centile, ball skills 1st centile, static and dynamic balance 5th centile). This case demonstrates that GLUT1-DS should be investigated in individuals with unexplained developmental delay. Epilepsy is not a mandatory symptom. The ketogenic diet is also beneficial for non-epileptic symptoms in GLUT1-DS.

Milder phenotypes of glucose transporter type 1 deficiency syndrome.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a treatable condition resulting from impaired glucose transport into the brain. The classical presentation is with infantile-onset epilepsy and severe developmental delay. Non-classical phenotypes with movement disorders and early-onset absence epilepsy are increasingly recognized and the clinical spectrum is expanding. The hallmark is hypoglycorrhachia (cerebrospinal fluid [CSF] glucose<2.2 mmol/l) in the presence of normoglycaemia with a CSF/blood glucose ratio of less than 0.4. GLUT1DS is due to a mutation in the solute carrier family 2, member 1 gene (SLC2A1). We present five individuals (four males, one female), all of whom had a mild phenotype, highlighting the importance of considering this diagnosis in unexplained neurological disorders associated with mild learning difficulties, subtle motor delay, early-onset absence epilepsy, fluctuating gait disorders, and/or dystonia. The mean age at diagnosis was 8 years 8 months. This paper also shows phenotypical parallels between GLUT1DS and paroxysmal exertion-induced dyskinesia.

Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain-- a review.

UNLABELLED: Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome (MIM 138140) defines a prototype of a novel group of disorders resulting from impaired glucose transport across blood-tissue barriers. It is caused by a defect in glucose transport into brain, mediated by the facilitative glucose transporter GLUT1. Since 1991, more than 70 patients have been identified. The hallmark of the disease is a low glucose concentration in the CSF (hypoglycorrhachia) in the presence of normoglycaemia (CSF/blood glucose ratio <0.4). Clinical features are variable and include seizures, developmental delay, acquired microcephaly, hypotonia, and a complex motor disorder with elements of ataxia, dystonia, and spasticity. The GLUT1 defect can be confirmed in erythrocytes by glucose uptake studies and GLUT1 immunoreactivity, and by molecular analysis of the GLUT1 gene. Several heterozygous mutations resulting in GLUT1 haploinsufficiency have been identified. An effective treatment is available by means of a ketogenic diet as ketone bodies serve as an alternative fuel for the developing brain. CONCLUSION: this treatable condition should be suspected in children with unexplained neurological disorders associated with epilepsy and developmental delay and confirmed by a lumbar puncture.

In vivo and in vitro NMR spectroscopy reveal a putative novel inborn error involving polyol metabolism.

In vivo NMR spectroscopy was performed on the brain of a patient with a leukoencephalopathy, revealing unknown resonances between 3.5 and 4.0 ppm. In addition, urine and CSF of the patient were measured using high-resolution NMR spectroscopy. Also in these in vitro spectra, unknown resonances were observed in the 3.5-4.0 ppm region. Homonuclear (1)H two-dimensional J-resolved spectroscopy (JRES) and (1)H-(1)H correlation spectroscopy (COSY) were performed on the patient's urine for more accurate assignment of resonances. The NMR spectroscopic studies showed that the unknown resonances could be assigned to arabinitol and ribitol. This was confirmed using gas chromatography. The arabinitol was identified as D-arabinitol. The patient is likely to suffer from an as yet unknown inborn error of metabolism affecting D-arabinitol and ribitol metabolism. The primary molecular defect has not been found yet. Urine spectra of patients suffering from diabetes mellitus or galactosemia were recorded for comparison. Resonances outside the 3.2-4.0 ppm region, which are the most easy to recognize in body fluid spectra, allow easy recognition of various sugars and polyols. The paper shows that NMR spectroscopy in body fluids may help identifying unknown resonances observed in in vivo NMR spectra.