DEFICIENCIA DE GLUT1 PDF

Only comments seeking to improve the quality and accuracy of information on the Orphanet website are accepted. For all other comments, please send your remarks via contact us. Only comments written in English can be processed. Glucose transporter type 1 GLUT1 deficiency syndrome is characterized by an encephalopathy marked by childhood epilepsy that is refractory to treatment, deceleration of cranial growth leading to microcephaly, psychomotor retardation, spasticity, ataxia, dysarthria and other paroxysmal neurological phenomena often occurring before meals.

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Alternative titles; symbols. Other entities represented in this entry:. GLUT1 deficiency syndrome-1 is a neurologic disorder showing wide phenotypic variability. The most severe 'classic' phenotype comprises infantile-onset epileptic encephalopathy associated with delayed development, acquired microcephaly, motor incoordination, and spasticity. Onset of seizures, usually characterized by apneic episodes, staring spells, and episodic eye movements, occurs within the first 4 months of life.

Other paroxysmal findings include intermittent ataxia, confusion, lethargy, sleep disturbance, and headache. Varying degrees of cognitive impairment can occur, ranging from learning disabilities to severe mental retardation.

As more cases with GLUT1 deficiency syndrome were described, the phenotype was broadened to include individuals with ataxia and mental retardation but without seizures, individuals with dystonia and choreoathetosis, and rare individuals with absence seizures and no movement disorder. The disorder, which results from a defect in the GLUT1 glucose transporter causing decreased glucose concentration in the central nervous system, is part of a spectrum of neurologic phenotypes resulting from GLUT1 deficiency.

GLUT deficiency syndrome-2 represents the less severe end of the phenotypic spectrum and is associated with paroxysmal exercise-induced dystonia with or without seizures. Correct diagnosis of GLUT1 deficiency is important because a ketogenic diet often results in marked clinical improvement of the motor and seizure symptoms reviews by Pascual et al.

De Vivo et al. These symptoms suggested the existence of a defect in glucose transport across the blood-brain barrier. Wang et al. The deficiency in the transporter resulted in reduced cerebrospinal fluid glucose concentrations and reduced erythrocyte glucose transporter activities in the patients.

Rotstein et al. He developed recurrent limb stiffening and cyanosis at age 6 weeks. Seizures included tonic eye deviation, staring spells, myoclonic jerks, and prolonged and refractory generalized tonic-clonic seizures. He had delayed psychomotor development and progressive microcephaly. CSF showed hypoglycorrhachia. A ketogenic diet was helpful with seizure control, but at age 6 years, his developmental quotient was He had axial hypotonia, limb spasticity and dystonia, and severe ataxia.

Brockmann et al. Seizure frequency and severity were aggravated by fasting, and responded to a carbohydrate load. Ultimately, however, the seizures and motor disability in the patients responded best to a ketogenic diet Brockmann, Klepper and Voit provided a detailed review of GLUT1 deficiency, including clinical features, a diagnostic algorithm, and effective treatment strategies.

Seizure type varied and included generalized tonic or clonic, myoclonic, atypical absence, atonic, and unclassified. Seizures were unresponsive to typical anticonvulsant medication, but responded rapidly to a ketogenic diet. Patients with the classic phenotype also experienced other variable paroxysmal events, including confusion, lethargy, hemiparesis, ataxia, sleep disturbances, and headaches.

Cognitive impairment ranged from learning disabilities to severe mental retardation; some patients had impaired speech and language development. Neurologic signs showed variable involvement of the pyramidal, extrapyramidal, and cerebellar systems. Zorzi et al. None had a positive family history. All had global developmental delay noted in infancy, and 2 had seizures beginning in the first 6 months of life myoclonic absence and complex partial seizures, respectively.

All had microcephaly, dysarthria, spasticity, and moderate mental retardation. Paroxysmal movements included myoclonic jerks, stiffening, and dystonic posturing. The phenotype in the 2 patients with early-onset seizures was consistent with GLUT1DS1; the other patient did not have seizures, but had ataxia, spasticity, dystonia, and dysarthria, more similar to the phenotype observed in GLUT1 syndrome-2 Genetic analysis identified a different heterozygous mutation in the GLUT1 gene in each patient see, e.

Hully et al. Detailed retrospective clinical information was available for 24 patients. The patients came to medical attention at a median age of 7. Seizures started between 1. Sensitivity to fasting or exertion was a prominent feature. Patients with myoclonic seizures had more severe intellectual disability.

Many movements affected the buccofacial area and eye movements. The phenotype tended change over time: epilepsy tended to decrease with age, while movement disorders and paroxysmal exercise-induced dystonia and dyskinesias worsened with age. Missense mutations were associated with a less severe phenotype. Mullen et al. Three of the patients fulfilled the narrow definition of MAE, and 1 fit a broader definition. The first 3 patients had onset of multiple seizure types, including myoclonic-atonic seizures, by age 3 years, and subsequent cognitive decline, resulting in severe intellectual disability in patients 1 and 3.

Patient 2, who was treated early with a ketogenic diet, had mild intellectual disability. The patient with the broader definition of MAE had onset at age 4 years of atonic and absence seizures, followed by a progressive epileptic encephalopathy and mild intellectual disability. Two of the patients also developed paroxysmal exertional dyskinesia in childhood. The findings were important because GLUT1 deficient patients can be treated with a ketogenic diet.

Yang et al. Among those with defects, there was a significant inverse correlation between median values of uptake and clinical severity. The findings validated the erythrocyte glucose uptake assay as a confirmatory functional test for GLUT1 deficiency and as a surrogate marker for GLUT1 haploinsufficiency.

In a review, Klepper and Leiendecker proposed diagnostic criteria for GLUT1 deficiency syndrome: seizures, developmental delay, complex movement disorder, and fasting EEG changes that improve postprandially. Pascual et al. The woman had an unaffected twin sister who served as a control. Both patients had residual encephalopathy with hypertonicity, dysarthria, hyperreflexia, ataxia, mental retardation, and microcephaly.

Neuropsychologic testing revealed decreased IQ, articulation difficulties, and friendly demeanor in both patients. The authors hypothesized that glucose serves a dual capacity in the developing brain, acting both as a fuel and as a signaling molecule.

Klepper et al. In the family reported by Brockmann et al. The syndrome behaved as an autosomal dominant, with 1 instance of father-to-son transmission. Rare cases of autosomal recessive transmission have been reported Wang et al. The patient reported by Klepper et al. She was noted to have unsteady ataxic gait at age 18 months, as well as paroxysmal choreoathetosis.

She also had developmental delay and hypotonia. EEG showed a polymorphic baseline alpha-theta activity with an isolated monomorphic sharp wave focus. Lumbar puncture showed hypoglycorrhachia and decreased CSF lactate. Her asymptomatic 2-year-old sister was also homozygous for the mutation; she was found to have hypoglycorrhachia and decreased CSF lactate.

The parents, who were unaffected, were heterozygous for the mutation. The findings suggested that GLUT1 deficiency can also be inherited in an autosomal recessive pattern. All 4 were started on a ketogenic diet at 6 to 28 weeks of age.

Ketosis developed within 24 hours. The ketogenic formula was tolerated well, parental compliance was good, and all patients remained seizure-free on the diet. One infant developed failure to thrive on medium-chain triglycerides, which was reversed using long-chain triglycerides. Adverse effects of the diet were limited to renal stones in 1 patient.

They concluded that ethanol, diazepam, chloralhydrate, phenobarbital, and pentobarbital could exacerbate the effect of GLUT1 deficiency on glucose transport into the brain, whereas phenytoin and carbamazepine had no significant inhibitory effects and might be preferable for use in seizure control. They noted that recommendations should be viewed with caution as the data did not assess cerebral glucose utilization. Two patients had recurrence of seizures after 2.

Seidner et al. Homozygous mutant mice were embryonic lethal. Brockmann, K. The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev. Autosomal dominant Glut-1 deficiency syndrome and familial epilepsy. De Vivo, D. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. New Eng. Hully, M. From splitting GLUT1 deficiency syndromes to overlapping phenotypes.

Klepper, J. GLUT1 deficiency syndrome update. Child Neurol. Introduction of a ketogenic diet in young infants. Autosomal recessive inheritance of GLUT1 deficiency syndrome.

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Alternative titles; symbols. Other entities represented in this entry:. GLUT1 deficiency syndrome-1 is a neurologic disorder showing wide phenotypic variability. The most severe 'classic' phenotype comprises infantile-onset epileptic encephalopathy associated with delayed development, acquired microcephaly, motor incoordination, and spasticity. Onset of seizures, usually characterized by apneic episodes, staring spells, and episodic eye movements, occurs within the first 4 months of life.

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Mount LA, Reback S. Familial paroxysmal choreoathetosis: Preliminary report on a hitherto undescribed clinical syndrome. Arch Neurol Psychiatry ; Lance JW. Familial paroxysmal dystonic choreoathetosis and its differentiation from related syndromes. Ann Neurol ; 2: N Engl J Med ;

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Seizures may be just one symptom of a rare genetic disorder called glucose transporter type 1 deficiency syndrome Glut1 DS. Many neurologic conditions share the symptoms of glucose transporter type 1 deficiency syndrome Glut1 DS , a rare genetic disorder. In people with Glut1 DS, glucose is not adequately transported from the bloodstream into brain cells. Because glucose is the primary source of energy for the brain, the brain receives inadequate energy in people affected by Glut1 DS.

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