UNLABELLED: Glucose transporter 1 deficiency syndrome (GLUT1DS) is an autosomal dominant disorder of brain energy metabolism caused by impaired GLUT1-mediated glucose transport across the blood-brain barrier. Although the clinical spectrum of this disorder is expanding rapidly, the growth patterns and endocrine status of these patients are not well known. We report the case of a boy aged 12 years and 7 months who has GLUT1DS complicated by growth failure. His failure to grow had progressed since birth, and his body height was 125 cm (-3.6 SDS). Growth hormone stimulation tests showed severe growth hormone deficiency (GHD), and we initiated GH replacement therapy. After 2 years of treatment, the boy's growth rate recovered from 1.7 cm/year before treatment, to 7.5 cm/year and 4.3 cm/year after treatment with no adverse effects. We speculate that GHD is a possible complication of GLUT1DS and discuss the underlying causative mechanism.
CONCLUSION: GHD may be a possible complication of GLUT1DS.
Glucose transporter type 1 deficiency syndrome is characterized by infantile onset seizures, development delay, movement disorders, and acquired microcephaly. The phenotype includes allelic variants such as intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia of childhood with or without epilepsy. Dystonias involve allelic variants of glucose transporter type 1 deficiency syndrome. Three Chinese patients presented with paroxysmal behavioral disturbance, weakness, ataxia (especially after fasting), and exercise intolerance. Electroencephalogram findings did not correlate with clinical manifestations. Cranial magnetic resonance imaging produced normal results or mild hypomyelination. Hypoglycorrhachia was evident in all cases. Cerebrospinal fluid glucose ranged from 1.63-2.45 mmol/L. Erythrocyte 3-O-methyl-d-glucose uptake was decreased to 58% in patient 1. Three SLC2A1 disease-causing mutations (761delA, P383H, and R400C) were observed. No patient tolerated ketogenic diets. Two patients responded to frequent meals with snacks. Cerebrospinal fluid evaluation constitutes the diagnostic testing permitting early treatment of glucose transporter type 1 deficiency syndrome. Early diagnosis and treatment improve prognoses.
Glucose transporter-1 (GLUT1) deficiency syndrome is caused by heterozygous mutations in the SLC2A1 gene, resulting in impaired glucose transport into the brain. It is characterized by a low glucose concentration in the cerebrospinal fluid (hypoglycorrhachia) in the absence of hypoglycemia, in combination with low to normal lactate in the cerebrospinal fluid (CSF). It often results in treatment-resistant infantile epilepsy with progressive developmental disabilities and a complex movement disorder. Recognizing GLUT1 deficiency syndrome is important, since initiation of a ketogenic diet can reduce the frequency of seizures and the severity of the movement disorder. There can be a considerable delay in diagnosing GLUT1 deficiency syndrome, and this point is illustrated by the natural history of this disorder in a 21-year-old woman with severe, progressive neurological disabilities. Her encephalopathy consisted of treatment-resistant seizures, a complex movement disorder, progressive intellectual disability, and deceleration of her head growth after late infancy. Focused evaluation at age 21 revealed GLUT1 deficiency caused by a novel heterozygous missence mutation in exon 7 (c.938C > A; p.Ser313Try) in SLC2A1 as the cause for her disabilities.
Glucose transporter type 1 deficiency syndrome is an inborn error of glucose transport across blood–tissue barriers, and the modified Atkins diet is an effective and well-tolerated treatment. To investigate the effects of the modified Atkins diet, we examined the cerebrospinal fluid markers and performed phosphorus magnetic resonance spectroscopy in a patient with glucose transporter type 1 deficiency syndrome before and after the modified Atkins diet. Cerebrospinal fluid levels of the oxidative stress markers, 8-hydroxy-2′-deoxyguanosine and hexanoyl-lysine adduct, were markedly increased above the cutoff index and were normalized 18 months after the modified Atkins diet. Phosphorus magnetic resonance spectroscopy measurements showed 18% increase of PCr/γ-ATP ratio after the modified Atkins diet. These results suggest that the modified Atkins diet may reduce oxidative stress in the brain and improve energy reserve capacity, which is important in sustaining electrophysiological activities essential for performing brain functions.
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 (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<2.2mmol/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.
Glucose transporter type 1 deficiency syndrome (GLUT1DS) is an inborn error of brain energy metabolism characterized by impaired glucose transport into the brain. A classic phenotype comprising epilepsy, mental retardation, an often paroxysmal disorder, and several subtypes has been described. Although typical absences are frequent in GLUT1DS, myoclonic absence seizures are rarely reported. Here we describe a novel Turkish patient with a hot-spot mutation (R126C) in the SLC2A1 gene who presented with unusual myoclonic absence epilepsy and paroxysmal shivering. The case is discussed in view of eight other cases carrying the R126C mutation.
PURPOSE: Glucose transporter type 1 (Glut1) is expressed in vascular endothelial cells comprising blood-brain barrier. Glut1 deficiency syndrome is characterized by low cerebrospinal fluid (CSF) concentration of glucose with normoglycemia, infantile seizure, acquired microcephaly, developmental delay and ataxia. As Glut1 is also expressed in erythrocytes, the diagnosis is confirmed by a decreased uptake of 3-O-methylglucose (3-OMG) into erythrocytes. However, patients with T295M mutation in the Glut1 gene show normal 3-OMG uptake. An in vitro study has proved that the T295M affects efflux rather than influx of glucose, explaining the discrepancy. However, the normal 3-OMG uptake in erythrocytes still indicates a possibility that the phenotype associated with this particular mutation may be milder. We compared the phenotype of three T295M-associated patients with that of other Glut1-deficient patients.
PATIENTS AND METHODS: Two patients are from our clinic and one is a patient reported elsewhere. The phenotype and biochemical data of patients with mutations other than T295M were obtained from a review and our previous report.
RESULTS: Despite the normal 3-OMG uptake into erythrocytes, all patients with T295M showed decreased glucose levels in CSF (33, 31 and 38mg/dl, respectively). The levels were comparable to those in patients with mutations other than T295M (31±4.3mg/dl (n=45)). All patients had convulsion, ataxia, speech delay, microcephaly and spasticity.
CONCLUSION: Despite the normal 3-OMG uptake in erythrocytes, phenotype of T295M-associated Glut1 deficiency was not significantly different from that of patients with a deficient 3-OMG uptake, indicating that T295M affects the glucose transport at the blood-brain barrier as much as other mutations.
AIM: Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a metabolic encephalopathy that can be effectively treated with a ketogenic diet. The aim of this study was to consolidate the effectiveness of the modified Atkins diet (MAD) as an alternative treatment for GLUT1-DS.
METHOD: Six Japanese males with GLUT1-DS were selected for treatment with the MAD. Their age at the time the MAD was instituted ranged from 7 to 16 years and the duration of treatment ranged from 1 to 42 months. All participants had early-onset epilepsy. Each participant's neuropsychological activity, seizure frequency, neurological status, and electroencephalographic (EEG) findings were compared before and after the introduction of the MAD.
RESULTS: After initiation of the treatment, all individuals showed +2 to +3 urinary ketosis on a ketostick test check. Epileptic seizures and other paroxysmal events decreased markedly in all individuals. Interictal EEG showed improvement in the background activity and disappearance of epileptic discharges. Along with an increased vigilance level, improvement in motivation and cognitive function was also achieved. Non-paroxysmal permanent ataxia, spasticity, dysarthria, and dystonia were moderately improved in four individuals and slightly improved in the remaining two. Preprandial transient aggravation of neurological symptoms completely disappeared in all participants. There were no significant side effects.
INTERPRETATION: For the treatment of GLUT1-DS, the MAD is less restrictive, more palatable, and easier to maintain than the conventional ketogenic diet, but its effectiveness was similar. Thus, MAD treatment is promising for individuals with GLUT1-DS and their families.
Glucose transporter 1 deficiency syndrome (GLUT1DS) is an autosomal dominant disorder of brain energy metabolism caused by impaired GLUT1-mediated glucose transport across the blood-brain barrier. Although the clinical spectrum of this disorder is expanding rapidly, the growth patterns and endocrine status of these patients are not well known. We report the case of a boy aged 12 years and 7 months who has GLUT1DS complicated by growth failure. His failure to grow had progressed since birth, and his body height was 125 cm (-3.6 SDS). Growth hormone stimulation tests showed severe growth hormone deficiency (GHD), and we initiated GH replacement therapy. After 2 years of treatment, the boy's growth rate recovered from 1.7 cm/year before treatment, to 7.5 cm/year and 4.3 cm/year after treatment with no adverse effects. We speculate that GHD is a possible complication of GLUT1DS and discuss the underlying causative mechanism.
