Wilhelmina G. Leen

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.

Cerebrospinal Fluid Glucose and Lactate: Age-Specific Reference Values and Implications for Clinical Practice

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 5–95th percentile ranges. CSF glucose 5th percentile values ranged from 1.8 to 2.9 mmol/L and 95th percentile values from 3.8 to 5.6 mmol/L. CSF/plasma glucose ratio 5th percentile values ranged from 0.41 to 0.53 and 95th percentile values from 0.82 to 1.19. CSF lactate 5th percentile values ranged from 0.88 to 1.41 mmol/L and 95th 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.

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.

Rituximab and intravenous immunoglobulins for relapsing postinfectious opsoclonus-myoclonus syndrome.

We describe 2 children with postinfectious opsoclonus-myoclonus syndrome. Although the patients initially responded to monotherapy with methylprednisolone, intravenous immunoglobulins, or rituximab, they manifested persistent neurologic deficits and relapsing signs. Treatment with rituximab in combination with intravenous immunoglobulin, however, resulted in significant longterm clinical improvement.

Ptosis as a feature of late-onset glycogenosis type II.

PTOSIS AS A FEATURE OF LATE-ONSET GLYCOGENOSIS TYPE II To the Editor: Groen et al.1 describe unilateral myogenic ptosis in 4/12 (33%) adults with type II glycogenosis. Ptosis was the presenting symptom in three out of four patients suggesting that it may help in the early diagnosis of the disease. We describe a woman with genetically defined type II glycogenosis in whom ptosis preceded by 2 years the development of skeletal muscle weakness. Our patient developed unilateral ptosis at 46 years of age, when the only muscle symptom was abnormal fatigability during stair climbing. At 48, she began to complain of walking difficulties. Neurologic examination showed proximal lower limb muscle weakness (4/5 onMRC score), unilateral ptosis, and raised CK levels (220 U/L, normal 24 to 204), suggesting mitochondrial myopathy. However, examination of a muscle biopsy revealed increased glycogen content and acid maltase deficiency (0.10 nmol/min/mg, normal 3 to 15). Sequence analysis of the alpha glucosidase gene showed a compound heterozygous mutant genotype IVS1 (13T G)/ 525delT. Family history was negative for neurologic abnormalities. Ocular movements and pupillary reflexes were normal. No abnormality was present by brain and orbital MRI, chest CT scan, and singlefiber EMG of the orbicularis oculi. Ptosis became bilateral at 58 years and is now severe at 60: the vertical width of the eyelid fissure at rest is 3 mm on the right and 5 mm on the left; under maximal activity of the levator palpebrae the width is 5 mm on the right and 7 mm on the left. In spite of proximal lower limb weakness (MRC: 3/5), the patient still walks unassisted but her upright vital capacity is decreased by 52%. The ptosis has remained unmodified after 2 months of therapy with Myozyme. Similar to the patients described by Groen et al., our patient developed ptosis at an early stage of the disease. However, in our series of 22 patients, she was the only one who developed ptosis. Full genetic analysis was completed for 17/22 cases: a second female patient with the same genotype has no ptosis. If the data by Groen et al. are combined with those of our series, ptosis was present in 5 cases (4 women) out of 34 (14.7%), and was consistently an early onset clinical sign. It does not seem to be associated with any specific mutation; all patients shared the common IVS1 (13T G), while the 525delT was present in two patients with and in five without ptosis.

Movement disorders in GLUT1 deficiency syndrome respond to the modified Atkins diet.

Movement disorders are a prominent feature of glucose transporter‐1 (GLUT1) deficiency syndrome (GLUT1DS). First‐choice treatment is a ketogenic diet, but compliance is poor. We have investigated the effect of the modified Atkins diet as an alternative treatment for movement disorders in GLUT1DS.

A novel SLC2A1 mutation linking hemiplegic migraine with alternating hemiplegia of childhood

Background Hemiplegic migraine (HM) and alternating hemiplegia of childhood (AHC) are rare episodic neurological brain disorders with partial clinical and genetic overlap. Recently, ATP1A3 mutations were shown to account for the majority of AHC patients. In addition, a mutation in the SLC2A1 gene was reported in a patient with atypical AHC. We therefore investigated whether mutations in these genes may also be involved in HM. Furthermore, we studied the role of SLC2A1 mutations in a small set of AHC patients without ATP1A3 mutations. Methods We screened 42 HM patients (21 familial and 21 sporadic patients) for ATP1A3 and SLC2A1 mutations. In addition, four typical AHC patients and one atypical patient with overlapping symptoms of both disorders were screened for SLC2A1 mutations. Results A pathogenic de novo SLC2A1 mutation (p.Gly18Arg) was found in the atypical patient with overlapping symptoms of AHC and hemiplegic migraine. No mutations were found in the HM and the other AHC patients. Conclusion Screening for a mutation in the SLC2A1 gene should be considered in patients with a complex phenotype with overlapping symptoms of hemiplegic migraine and AHC.

Child Neurology: Differential diagnosis of a low CSF glucose in children and young adults

Analysis of CSF is daily routine in patients with acute neurologic disorders like CNS infections. In those patients, the finding of a low CSF glucose may influence further diagnostic workup and therapeutic choices. The interpretation of a low CSF glucose in patients with a chronic neurologic disorder, however, is a less common practice. We present a practical overview on the differential diagnosis of a low CSF glucose and stress the importance of recognizing a low CSF glucose as the diagnostic marker for GLUT1 deficiency syndrome, a treatable neurometabolic disorder.

Hourly analysis of cerebrospinal fluid glucose shows large diurnal fluctuations

Cerebrospinal fluid analysis is important in the diagnostics of many neurological disorders. Since the influence of food intake on the cerebrospinal fluid glucose concentration and the cerebrospinal fluid/plasma glucose ratio is largely unknown, we studied fluctuations in these parameters in healthy adult volunteers during a period of 36 h. Our observations show large physiological fluctuations of cerebrospinal fluid glucose and the cerebrospinal fluid/plasma glucose ratio, and their relation to food intake. These findings provide novel insights into the physiology of cerebral processes dependent on glucose levels such as energy formation (e.g. glycolysis), enzymatic reactions (e.g. glycosylation), and non-enzymatic reactions (e.g. advanced endproduct glycation).