Unusual phenotype of glucose transport protein type 1 deficiency syndrome: A case report and literature review.

The glucose transport protein type 1 (GLUT1) deficit causes a chronic brain energy failure. The classic phenotype of GLUT1 deficiency syndrome is characterized by: Mild to severe motor delay and mental retardation; infantile-onset epilepsy; head growth deceleration; movement disorders (ataxia, dystonia, spasticity); and non-epileptic paroxysmal events (intermittent ataxia, periodic confusion, recurrent headaches). During last years the classic phenotype of this syndrome, as originally reported, has expanded. We report the atypical phenotype of a boy with GLUT1 deficiency syndrome, characterized by mild mental retardation and drug-resistant absence seizures with onset at the age of 6 years, without movement disorders nor decrease of head circumference. A prompt diagnosis of this disorder is mandatory since the ketogenic diet might represent an effective treatment.

Introduction

Glucose transport protein type 1 (GLUT1) delivers glucose to the brain from bloodstream and is therefore crucial for an adequate energy provision.[123456] GLUT1 deficiency syndrome, inducing a chronic brain energy failure, is caused by mutations of the solute carrier family 2 (facilitated glucose transporter) member 1 (SLC2A1) gene, located on the chromosome 1p34.2. Most mutations are de novo; inheritance in familial cases is mostly autosomal dominant.[23456]

The classic phenotype of GLUT1 deficiency syndrome is characterized by: Mild to severe motor delay and mental retardation; infantile-onset epilepsy; head growth deceleration, possibly resulting in acquired microcephaly; movement disorders (ataxia, dystonia, spasticity); and non-epileptic paroxysmal events (intermittent ataxia, periodic confusion, recurrent headaches).[12] Reported features of epilepsy in this condition are heterogeneous; generalized tonic-clonic and absence seizures prevail.[7] Lumbar puncture shows hypoglycorrhachia, with a reduced cerebrospinal fluid/blood glucose ratio in most patients. The ketogenic diet has proved to markedly improve epilepsy, movement disorders and head growth, while the cognitive effects are less pronounced.[123456]

We describe the atypical phenotype of a boy with GLUT1 deficiency syndrome.

Case Report

The patient's family history was positive for: A not better specified psychiatric disorder and somnambulism in the mother; epilepsy and mental retardation, in a paternal uncle and a paternal cousin, respectively. The mother had some spontaneous abortions. He was an only child, born at the 36th week of gestation by Caesarean section due to hypertensive gestosis, after a two-placenta twin pregnancy, with the intrauterine death of the other fetus. Apgar Index was 7 (1’) and 8 (5’); birth weight was 3040 grams. Cyanosis and jaundice at the birth were reported; jaundice was treated by phototherapy and exsanguinotransfusion. He had a bilateral nuclear congenital cataract. Height and weight growth were normal. There was a mild, global delay of psychomotor development. At the age of 4 years 1 month, EEG tracing during wakefulness, performed due to the psychomotor retardation, was normal. From the age of about 4 years he has suffered from headache several times monthly, sometimes associated with nausea and vomiting, treated with paracetamol. At the age of about 6 years, he started to present, especially in the morning, short but frequent (even several times a day) episodes of loss of consciousness, eye closure, inconstant eyelid myoclonia. The events could occur isolated or close together resulting in falling asleep but showing amelioration on awakening. The drowsiness associated with the long clusters of these events was a major problem in his everyday life, especially at school. When he came to our observation, he was 9 years 8 months old. Neurological examination showed only a mild, aspecific incoordination; head circumference corresponded to the fiftieth percentile. He often appeared tired, sleepy, and lazy. Neuropsychological evaluation showed a mild mental retardation (Wechsler Scale), stable during the follow-up, with a significant prevalence of verbal intelligence quotient (IQ) versus performance IQ; an aspecific learning disorder was evident. EEG revealed diffuse paroxysmal abnormalities and several brief absence seizures have been recorded [Figures 1 and 2]. Electromyography as well as motor and sensory nerve conduction study was normal. Brain MRI was normal. High-resolution kariotype and search for fragile X syndrome were normal, as well as a metabolic screening including creatine kinase, lactic acid at baseline and after exercise, thyroid hormones, tests for celiac disease, ammonia, serum and urinary aminoacids, and urinary oligosaccharides. Absence seizures were drug resistant to ethosuximide, levetiracetam, lamotrigine, and valproate, with only transient improvements after beginning a drug. After antiepileptic therapy start, we found episodic, mild postural and tremor-like action dyskinesias in the arms. At the age of 15 years, mainly due to the drug-resistant absence seizures, we performed the molecular analysis of the SLC2A1 gene. The polymerase chain reaction sequencing of all exons revealed a nucleotide deletion in heterozygosity, “c.1336_1338del”, causing the loss of one amino acid (isoleucine: p.Ile446del). Genetic testing was negative in both parents. We chose not to give the lumbar puncture to avoid causing the patient excessive discomfort. A ketogenic diet was started and we noted a fast, marked clinical improvement. The boy became more responsive and active, while absence seizures and headache frequency decreased. However, patient's compliance with the prescribed dietary regimen was so poor that after 1 year we decided to stop the diet. Only a few days after the discontinuation, the boy showed clinical worsening, which made him willing to resume the diet.

Figure 1

EEG recording, at the age of 14 years, showing diffuse bilateral and frontal dominant spike and wave discharges during wakefulness: open eyes on the left, closed eyes on the right

Figure 2

EEG recording, at the age of 14 years, showing diffuse bilateral spikes and waves during hyperpnea, once associated (see arrows) with a brief absence seizure

Discussion

A constant supply of glucose is the most important source of energy for the brain. Therefore, GLUT1 deficiency syndrome could be considered as a brain energy failure prototype. During last years the classic phenotype of this syndrome, as originally reported, has expanded. Also the three following clinical pictures have been described: (a) carbohydrate-responsive phenotype, characterized by clinical worsening (motor and mental performance, seizures) with fasting and improvement with carbohydrate intake; (b) movement disorder without epilepsy, characterized by ataxia, dystonia, spasticity, mild delay of motor and mental development, normal or decelerated head growth; (c) paroxysmal exertion-induced dyskinesias (dystonia, choreoathetosis, ballism) and epilepsy.[2]

The case we have described shows an atypical phenotype of GLUT1 deficiency syndrome. No movement disorders were present (except for slight tremor after antiepileptic therapy start, probably a side effect of antiepileptic drugs), nor decrease of head circumference has been detected. The phenotype of our patient does not fully fit in any of the clinical pictures described so far in association with GLUT1 deficiency. In 2010, Leen et al. reported 10 cases with the so-called late-onset classical phenotype, but only in one of them movement disorders were absent and the reported features of seizures were different compared to those of our patient.[8] It is true that epilepsy with the absence seizures is among those most frequently described in GLUT1 deficiency syndrome, but more often it has an early onset (before the age of 4), while in the forms with later onset, as in our patient, the combination of drug-resistant absence seizures (without other types of seizures) and mental retardation, present in the case we have reported, has not been described.[79101112] Considering the findings of our patient's EEG (initially normal, then clearly pathological), our data confirm what Pong et al. stated,[7] namely that in the same individual, affected by this disorder, EEG picture could change over time. Our case report suggests that, in the lack of a better definition of the possible phenotypes associated with GLUT1 deficiency, there is a risk of underestimating the actual occurrence of the disease. Especially because of the atypical phenotypes, still today a high number of cases probably go undiagnosed. This fact has important implications also for the treatment, because a ketogenic diet, that should begin as soon as possible, could significantly improve the quality of life of these patients, while classic antiepileptic drugs usually fail. In fact, a high-fat diet leads to the production of ketone bodies bypassing the GLUT1 deficiency and providing an alternative source of energy to the brain.[123456] Incidentally, we emphasize that the exact pathogenetic mechanism of the formation of cataracts, also present in our patient, is currently unknown.[6]

In conclusion, clinical phenotype of GLUT1 deficiency syndrome needs further investigations. It is recommended to consider this diagnostic hypothesis in any case with an unexplained neurological disorder,[211] also when, as in our case, a main clinical feature consists of drug-resistant seizures associated with a global developmental delay, even in the lack of a movement disorder, according to Klepper suggestions.[4]