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Encephalopathy due to GLUT1 deficiency(GLUT1DS1)

MedGen UID:
1645412
Concept ID:
C4551966
Disease or Syndrome
Synonyms: De Vivo disease; Glucose transport defect, blood-brain barrier; Glucose transporter protein syndrome; GLUT1 deficiency syndrome 1; GLUT1 deficiency syndrome 1, infantile onset, severe
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): SLC2A1 (1p34.2)
 
Monarch Initiative: MONDO:0011724
OMIM®: 606777
Orphanet: ORPHA71277

Disease characteristics

Excerpted from the GeneReview: Glucose Transporter Type 1 Deficiency Syndrome
The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS) is now known to be a continuum that includes the classic phenotype as well as paroxysmal exercise-induced dyskinesia and epilepsy (previously known as dystonia 18 [DYT18]) and paroxysmal choreoathetosis with spasticity (previously known as dystonia 9 [DYT9]), atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures in classic early-onset Glut1 DS begin before age six months. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified. In some infants, apneic episodes and abnormal episodic eye-head movements similar to opsoclonus may precede the onset of seizures. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continual with fluctuations in severity influenced by environmental factors such as fasting or with infectious stress. Symptoms often improve substantially when a ketogenic diet is started. [from GeneReviews]
Authors:
Dong Wang  |  Juan M Pascual  |  Darryl De Vivo   view full author information

Additional description

From OMIM
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. Hypoglycorrhachia (low CSF glucose, less than 40 mg/dl) and low CSF lactate are essentially diagnostic for the disorder. 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 (612126) 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., 2004 and Brockmann, 2009).  http://www.omim.org/entry/606777

Clinical features

From HPO
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Confusion
MedGen UID:
3587
Concept ID:
C0009676
Mental or Behavioral Dysfunction
Lack of clarity and coherence of thought, perception, understanding, or action.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Hemiparesis
MedGen UID:
6783
Concept ID:
C0018989
Finding
Loss of strength in the arm, leg, and sometimes face on one side of the body. Hemiplegia refers to a complete loss of strength, whereas hemiparesis refers to an incomplete loss of strength.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterest, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Sleep abnormality
MedGen UID:
52372
Concept ID:
C0037317
Finding
An abnormal pattern in the quality, quantity, or characteristics of sleep.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Paroxysmal dystonia
MedGen UID:
97951
Concept ID:
C0393588
Sign or Symptom
A form of dystonia characterized by episodes of dystonia (often hemidystonia or generalized) lasting from minutes to hours. There are no dystonic symptoms between episodes.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Paralysis
MedGen UID:
105510
Concept ID:
C0522224
Finding
Paralysis of voluntary muscles means loss of contraction due to interruption of one or more motor pathways from the brain to the muscle fibers. Although the word paralysis is often used interchangeably to mean either complete or partial loss of muscle strength, it is preferable to use paralysis or plegia for complete or severe loss of muscle strength, and paresis for partial or slight loss. Motor paralysis results from deficits of the upper motor neurons (corticospinal, corticobulbar, or subcorticospinal). Motor paralysis is often accompanied by an impairment in the facility of movement.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Hypoglycorrhachia
MedGen UID:
488927
Concept ID:
C0598121
Finding
Abnormally low glucose concentration in the cerebrospinal fluid.
Paroxysmal lethargy
MedGen UID:
335700
Concept ID:
C1847507
Finding
Repeated episodes of sudden-onset and transient lethargy.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Specific learning disability
MedGen UID:
871302
Concept ID:
C4025790
Mental or Behavioral Dysfunction
Impairment of certain skills such as reading or writing, coordination, self-control, or attention that interfere with the ability to learn. The impairment is not related to a global deficiency of intelligence.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding
Paroxysmal involuntary eye movements
MedGen UID:
338246
Concept ID:
C1847515
Finding
Sudden-onset episode of abnormal, involuntary eye movements.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Veneruzzo GM, Loos MA, Armeno M, Alonso CN, Caraballo RH
Arch Argent Pediatr 2023 Feb 1;121(1):e202202677. Epub 2022 Nov 3 doi: 10.5546/aap.2022-02677.eng. PMID: 36315575
Zimmern V, Korff C
Curr Opin Pediatr 2022 Dec 1;34(6):538-543. Epub 2022 Sep 9 doi: 10.1097/MOP.0000000000001170. PMID: 36081356Free PMC Article
Falsaperla R, Sciuto L, La Spina L, Sciuto S, Praticò AD, Ruggieri M
Metab Brain Dis 2021 Dec;36(8):2195-2203. Epub 2021 Aug 17 doi: 10.1007/s11011-021-00798-1. PMID: 34403026Free PMC Article

Recent clinical studies

Etiology

Al-Ahmad AJ
Handb Exp Pharmacol 2023;281:141-156. doi: 10.1007/164_2023_645. PMID: 36943490
Striano P, Auvin S, Collins A, Horvath R, Scheffer IE, Tzadok M, Miller I, Kay Koenig M, Lacy A, Davis R, Garcia-Cazorla A, Saneto RP, Brandabur M, Blair S, Koutsoukos T, De Vivo D
Epilepsia 2022 Jul;63(7):1748-1760. Epub 2022 May 21 doi: 10.1111/epi.17263. PMID: 35441706Free PMC Article
Pearson TS, Pons R, Ghaoui R, Sue CM
Mov Disord 2019 May;34(5):625-636. Epub 2019 Mar 26 doi: 10.1002/mds.27655. PMID: 30913345
Mullen SA, Berkovic SF; ILAE Genetics Commission
Epilepsia 2018 Jun;59(6):1148-1153. Epub 2018 May 9 doi: 10.1111/epi.14042. PMID: 29741207
Vaudano AE, Olivotto S, Ruggieri A, Gessaroli G, De Giorgis V, Parmeggiani A, Veggiotti P, Meletti S
Neuroimage Clin 2017;13:446-454. Epub 2016 Dec 21 doi: 10.1016/j.nicl.2016.12.026. PMID: 28116237Free PMC Article

Diagnosis

Falsaperla R, Sciuto L, La Spina L, Sciuto S, Praticò AD, Ruggieri M
Metab Brain Dis 2021 Dec;36(8):2195-2203. Epub 2021 Aug 17 doi: 10.1007/s11011-021-00798-1. PMID: 34403026Free PMC Article
Pearson TS, Pons R, Ghaoui R, Sue CM
Mov Disord 2019 May;34(5):625-636. Epub 2019 Mar 26 doi: 10.1002/mds.27655. PMID: 30913345
Koch H, Weber YG
Epilepsy Behav 2019 Feb;91:90-93. Epub 2018 Jul 31 doi: 10.1016/j.yebeh.2018.06.010. PMID: 30076047
Mullen SA, Berkovic SF; ILAE Genetics Commission
Epilepsia 2018 Jun;59(6):1148-1153. Epub 2018 May 9 doi: 10.1111/epi.14042. PMID: 29741207
Klepper J
Handb Clin Neurol 2013;113:1689-94. doi: 10.1016/B978-0-444-59565-2.00036-8. PMID: 23622389

Therapy

Donohue KJ, Fitzsimmons B, Bruntz RC, Markussen KH, Young LEA, Clarke HA, Coburn PT, Griffith LE, Sanders W, Klier J, Burke SN, Maurer AP, Minassian BA, Sun RC, Kordasiewisz HB, Gentry MS
Neurotherapeutics 2023 Oct;20(6):1808-1819. Epub 2023 Sep 12 doi: 10.1007/s13311-023-01434-9. PMID: 37700152Free PMC Article
Striano P, Auvin S, Collins A, Horvath R, Scheffer IE, Tzadok M, Miller I, Kay Koenig M, Lacy A, Davis R, Garcia-Cazorla A, Saneto RP, Brandabur M, Blair S, Koutsoukos T, De Vivo D
Epilepsia 2022 Jul;63(7):1748-1760. Epub 2022 May 21 doi: 10.1111/epi.17263. PMID: 35441706Free PMC Article
Falsaperla R, Sciuto L, La Spina L, Sciuto S, Praticò AD, Ruggieri M
Metab Brain Dis 2021 Dec;36(8):2195-2203. Epub 2021 Aug 17 doi: 10.1007/s11011-021-00798-1. PMID: 34403026Free PMC Article
Tang M, Park SH, De Vivo DC, Monani UR
Ann Clin Transl Neurol 2019 Sep;6(9):1923-1932. Epub 2019 Aug 28 doi: 10.1002/acn3.50881. PMID: 31464092Free PMC Article
Patching SG
Mol Neurobiol 2017 Mar;54(2):1046-1077. Epub 2016 Jan 22 doi: 10.1007/s12035-015-9672-6. PMID: 26801191

Prognosis

Veneruzzo GM, Loos MA, Armeno M, Alonso CN, Caraballo RH
Arch Argent Pediatr 2023 Feb 1;121(1):e202202677. Epub 2022 Nov 3 doi: 10.5546/aap.2022-02677.eng. PMID: 36315575
Pearson TS, Pons R, Ghaoui R, Sue CM
Mov Disord 2019 May;34(5):625-636. Epub 2019 Mar 26 doi: 10.1002/mds.27655. PMID: 30913345
Nakamura S, Osaka H, Muramatsu S, Aoki S, Jimbo EF, Yamagata T
Mol Genet Metab 2015 Nov;116(3):157-62. Epub 2015 Aug 14 doi: 10.1016/j.ymgme.2015.08.006. PMID: 26304067
Ito Y, Takahashi S, Kagitani-Shimono K, Natsume J, Yanagihara K, Fujii T, Oguni H
Brain Dev 2015 Sep;37(8):780-9. Epub 2014 Dec 5 doi: 10.1016/j.braindev.2014.11.006. PMID: 25487684
Deng D, Xu C, Sun P, Wu J, Yan C, Hu M, Yan N
Nature 2014 Jun 5;510(7503):121-5. Epub 2014 May 18 doi: 10.1038/nature13306. PMID: 24847886

Clinical prediction guides

Markussen KH, Corti M, Byrne BJ, Vander Kooi CW, Sun RC, Gentry MS
J Neurochem 2024 May;168(5):728-743. Epub 2023 Aug 9 doi: 10.1111/jnc.15926. PMID: 37554056Free PMC Article
Al-Ahmad AJ
Handb Exp Pharmacol 2023;281:141-156. doi: 10.1007/164_2023_645. PMID: 36943490
Suzuki T, Ito Y, Ito T, Kidokoro H, Noritake K, Hattori A, Nabatame S, Natsume J
Pediatr Neurol 2022 Jul;132:23-26. Epub 2022 Apr 29 doi: 10.1016/j.pediatrneurol.2022.04.012. PMID: 35605310
Striano P, Auvin S, Collins A, Horvath R, Scheffer IE, Tzadok M, Miller I, Kay Koenig M, Lacy A, Davis R, Garcia-Cazorla A, Saneto RP, Brandabur M, Blair S, Koutsoukos T, De Vivo D
Epilepsia 2022 Jul;63(7):1748-1760. Epub 2022 May 21 doi: 10.1111/epi.17263. PMID: 35441706Free PMC Article
Falsaperla R, Sciuto L, La Spina L, Sciuto S, Praticò AD, Ruggieri M
Metab Brain Dis 2021 Dec;36(8):2195-2203. Epub 2021 Aug 17 doi: 10.1007/s11011-021-00798-1. PMID: 34403026Free PMC Article

Recent systematic reviews

Falsaperla R, Sciuto L, La Spina L, Sciuto S, Praticò AD, Ruggieri M
Metab Brain Dis 2021 Dec;36(8):2195-2203. Epub 2021 Aug 17 doi: 10.1007/s11011-021-00798-1. PMID: 34403026Free PMC Article
Leen WG, Taher M, Verbeek MM, Kamsteeg EJ, van de Warrenburg BP, Willemsen MA
J Neurol 2014 Mar;261(3):589-99. Epub 2014 Jan 12 doi: 10.1007/s00415-014-7240-z. PMID: 24413642
Leen WG, Wevers RA, Kamsteeg EJ, Scheffer H, Verbeek MM, Willemsen MA
JAMA Neurol 2013 Nov;70(11):1440-4. doi: 10.1001/jamaneurol.2013.3090. PMID: 23999624

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