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Glucose transporter type 1 deficiency syndrome

This is part of Rare diseases.

Diagnosis: Glucose transporter type 1 deficiency syndrome

Synonyms: GLUT1 deficiency syndrome


Publication date: 2012-08-21
Version: 1.1

The disease

In glucose transporter type 1 deficiency syndrome brain metabolism is impaired so that glucose is prevented from entering the brain. The symptoms vary substantially, but the most characteristic manifestations of the classical form include epileptic seizures, usually with onset in infancy, and delayed cognitive and motor development.

The disease was first described in 1991 by the American paediatric neurologist Darryl De Vivo and his associates. They described two infants who had epileptic seizures by the age of two months in combination with developmental delays in both cognitive and motor skills. Tests detected low levels of glucose in the cerebrospinal fluid of these children, and both had a mutation in a gene coding for the transport protein GLUT1.

Occurrence

Glucose transporter type 1 deficiency syndrome occurs worldwide, but its incidence remains unknown. In Sweden about 10 individuals have been diagnosed with the syndrome, but it is likely that many others may be affected but have not been accurately diagnosed.

Cause

The syndrome is caused by a mutation in SLC2A1, a gene located on the short arm of chromosome 1 (1p11.2-p13.2). This gene governs the production of (codes for) the glucose transport protein GLUT1, and a defective protein will impair the transport of glucose into the brain. There is a degree of correlation between the severity of the condition and the type of mutation. The rare autosomal recessive forms (see under “Heredity”) tend to be severe.

Glucose is the brain’s most important source of energy. In adults at rest, the brain metabolises approximately 20 per cent of glucose intake, while the corresponding rate in neonates is 80 per cent. In contrast with other tissues in the body, the brain cannot use fats or amino acids as sources of energy. The membrane-bound protein GLUT1 normally transports glucose across the blood-brain barrier. When the function of this protein is impaired, the brain becomes deficient in energy, and various symptoms arise.

Heredity

The pattern of inheritance of glucose transporter type 1 deficiency syndrome is often autosomal dominant. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.

Figure: Autosomal dominant inheritance

In most people the syndrome is caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children. In rare cases, gonadal mosaicism has been demonstrated in a parent, meaning that he or she can carry the mutation in some of his/her reproductive cells without becoming ill, but that there is a risk of passing on the mutation to his/her children.

Autosomal recessive inheritance has been reported in isolated cases. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and, like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Symptoms

The severity of the disorder varies considerably. The onset is in childhood, but there are adults who have the syndrome but have not been accurately diagnosed. The most severe forms are characterised by significant intellectual disability, motor development delay, and epilepsy. Children with the mildest forms have normal cognitive development, and motor symptoms are mild. The condition tends to stabilise after puberty, with decreasing seizure activity. There is no indication that life expectancy is affected.

Classical form

The classical form of the syndrome is associated with early onset, occurring during the first year of life, manifesting as developmental delay, impaired motor control and deceleration of skull growth (acquired microcephaly). The onset of seizures generally occurs when the child is between three weeks and four months old, manifesting as spasms in the arms and/or legs, staring or rolling eye movements, short episodes of pallor, absent gaze or nodding.

The child may also have recurrent episodes of symptoms unrelated to the seizures, including balance and coordination problems (ataxia), confusion, headaches, or sleep disturbances.

All children develop some form of motor control problems, including shaking movements, ataxia and spasticity.

In most individuals there is no correlation between symptoms and food-intake or fasting.

Other forms

In some cases (carbohydrate responsive form), there is a clear correlation between fasting and aggravation of symptoms. This is noticeable as seizures intensify and loss of motor control occurs in response to fasting. Once carbohydrates are ingested, symptoms improve. The worst symptoms usually occur in the morning, before breakfast.

Sometimes the syndrome is not associated with epilepsy. Skull growth may also be normal. These children often have delayed motor and language development, speech problems (dysarthria), varying degrees of ataxia, involuntary muscle spasms (dystonia), and involuntary writhing movements (choreathetosis).

In some, the most characteristic symptom is the onset of paroxysmal dyskinesia following physical exertion. Dyskinesias are episodes of abnormal involuntary movements that do not affect consciousness. These movements may include spasms, writhing motions (choreathetosis) and explosive (ballistic) movements.

Often, but not always, these symptoms are combined with epilepsy and developmental delay. Migraines and isolated cases of haemolytic anaemia (resulting from abnormal breakdown of red blood cells), have also been reported.

In recent years it has been discovered that some cases of childhood absence epilepsy with onset before the age of four years are associated with Glucose transporter protein type 1 deficiency. These children usually have other types of seizures, as well as movement disorders or learning difficulties. Absence seizures are a common form of epilepsy in children, characterised by brief episodes of impaired consciousness and an absent gaze. For two to ten seconds, the child is unresponsive when spoken to. The onset of symptoms usually occurs between the ages of four and ten years. The classical form of childhood absence epilepsy is benign and children with this disorder usually grow out of it.

Diagnosis

Glucose transporter type 1 deficiency syndrome should be suspected if there is a combination of epilepsy, developmental delay, and movement disorders. The condition should also be suspected in other cases characterised by episodic symptoms, sometimes in combination with other manifestations.

The most important examination for confirming the diagnosis is to compare the cerebrospinal fluid (CSF) glucose value with the glucose concentration in blood. To attain a stable glucose level, fasting is recommended between four and six hours before the test is performed. To avoid stress-induced elevation of the glucose concentration, the blood sample should be drawn immediately before the cerebrospinal fluid. The lactase level is also checked on this occasion. The ratio between CSF glucose and serum glucose will be lower than normal, and the CSF lactate level will also be abnormally low.

Brain scans using magnetic resonance imaging (MRI) usually will not show any abnormalities. Sometimes the brain ventricles are slightly enlarged, and there may be a slight delay in the formation of the white matter of the brain (myelin).

EEG is usually normal. When abnormalities are detected, they often have the character of lateralized epileptiform discharges in infants, while children over the age of two years are more likely to display a generalized 2.5-4 Hz spike and wave pattern, and slow background activity. In carbohydrate-responsive forms (see under “Symptoms”), there are often considerable differences in the EEG patterns before and after a meal.

The diagnosis is established using DNA analysis that confirms the presence of a SLC2A1 mutation. Foetal diagnosis and embryo diagnosis are possible if the mutation in the family has been identified. At the same time that the diagnosis is made, the family should be offered genetic counselling.

In rare cases it may not be possible to confirm the diagnosis in a DNA analysis. Further tests can then be performed to assess the uptake of glucose in red blood cells.

Treatment/interventions

A ketogenic diet has proven effective in treating glucose transporter type 1 deficiency syndrome. This diet was developed at the Johns Hopkins hospital in Baltimore, USA. It implies a strict programme that includes food rich in fats, a minimum of carbohydrates, and the recommended daily intake of protein. The metabolism of surplus fat produces ketones, which can be used as an energy source for the brain instead of glucose.

There are different types of ketogenic diets. A simplified version has recently been introduced. The advantage is that it may be easier for the child to accept, as it does not include any restriction of calories, protein or liquid intake.

A ketogenic diet is usually an effective treatment for epileptic seizures, movement disorders and skull growth, but the effect on learning problems is less evident. Dietary treatment should be initiated as early as possible and continued throughout childhood. This is important, both to ensure that the high level of energy required by the developing brain is provided, and to minimise the risk of permanent damages. Regular contact with a dietician with special expertise in the ketogenic diet is required. Carnitine is often supplemented, as the ketogenic diet usually includes too little of this fat transport protein.

A strict ketogenic diet is associated with a risk of elevated blood fat levels, kidney stones, pancreatitis, heart problems, and platelet deficiencies. Regular, thorough examinations of the child must therefore be part of the follow-up of the condition, carried out at a university hospital unit of paediatric neurology.

Substances that inhibit GLUT1 function must be avoided. These include:

  • alcohol, coffee, green tea;
  • various types of medication, such as tricyclic antidepressants, certain types of anaesthesia, tyrosine kinase inhibitors (used for treating tumours), GTP analogues, certain types of anti-epileptic drugs (phenobarbital, chlorate hydrate, diazepam, valproate);
  • other substances, such as methylxantines (synthetic caffein), dioxine (an environmental pollutant that may, for example, be found in oily fish from the Baltic Sea), genistein (a dietary supplement extracted from the soy bean), androgens (male sex hormones, for example in anabolic steroids).

Other interventions focus on treating and alleviating symptoms, compensating for disabilities, and creating the best possible quality of life. Regular medical follow-up is important.

Epilepsy is medically treated with substances that do not inhibit GLUT1 function.

Children and families who require long-term habilitation should be in contact with a habilitation team made up of professionals with special expertise in how disability affects everyday life, health and development. The family may also need help coordinating interventions.

The habilitation team offers support and treatment within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It also includes information about support offered by the local authority as well as advice on the way accommodation and other environments can be adapted to the child’s needs. Parents and siblings can also receive support.

Habilitation plans are based on existing needs. Habilitation varies over time but always takes place in collaboration with those close to the child or young person.

The child’s ability to communicate and his or her capacity for social interaction must be assessed early. As speech problems and learning difficulties are common, assistance from a speech pathologist and educational support are important. The child’s special needs and developmental level determines which interventions are required. Some children need to learn to communicate using augmentative and alternative communication (AAC, a collective term for communication techniques not based on speech).

Children with motor impairments may need to practise daily life skills, such as mobility and dressing themselves. There are adaptations and aids that may be helpful.

Psychological support adapted to age and maturity should be available continuously through childhood. Even small children need their questions answered.

The local authority can offer different forms of support to facilitate the family’s everyday life.

Adults and young people with the syndrome require continued medical follow-up, and habilitation adapted to their invidudal needs. Those who have a late-onset form of the disorder should be in close contact with a neurology clinic.

Practical advice

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National and regional resources in Sweden

The diagnosis can be established at the child’s local hospital, after which a paediatric neurology unit at a university hospital should be consulted. Start-up and follow-up of the ketogenic diet is usually handled via a university hospital paediatric neurology unit.

Resource personnel

Associate Professor Niklas Darin, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: niklas.darin@vgregion.se.

Courses, exchanges of experience, recreation

Ågrenska is a national competence centre for rare diseases and its families’ programme arranges stays for children and young people with disabilities and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. A number of programmes is also provided every year for adults with rare diseases. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se

Organizations for the disabled/patient associations

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Gävlegatan 18 C, Box 6436, SE-113 82 Stockholm, Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

RBU, The Swedish National Association for Disabled Children and Young People, St Eriksgatan 44, Box 8026, SE-104 20 Stockholm, Sweden. Tel: +46 8 677 73 00, fax: +46 8 677 73 09, email: info@riks.rbu.se, www.rbu.se.

There is also the British association CLIMB (Children Living with Inherited Metabolic Diseases), email: info.svcs@climb.org.uk, www.climb.org.

Courses, exchanges of experience for personnel

During the Ågrenska Family Program weeks, training days are organized for personnel working with the children and young people who are participating in the program. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Research and development (R&D)

Research on this disorder is ongoing, both nationally and internationally. The foremost experts in the field are found at Columbia University, New York, USA, and in Göttingen, Germany.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. These leaflets may be ordered or printed out. (See under "Mer hos oss" in the right hand column.)

Newsletter from Ågrenska on glucose transporter type 1 deficiency syndrome, nr 428 (2012). Newsletters are edited summaries of lectures delivered at family and adult visits to Ågrenska. They can be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. Information is available on www.agrenska.se

Literature

Brockmann K, Wang D, Korenke CG, von Moers A, Ho YY, Pascual JM et al. Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. Ann Neurol 2001; 50: 476-485.

De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991; 325: 703-709.

Klepper J. Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet. Epilepsia 2008; 49 Suppl 8: 46-49.

Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste T, van Engelen BG et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain 2010; 133: 655-670.

Pons R, Collins A, Rotstein M, Engelstad K, De Vivo DC. The spectrum of movement disorders in Glut-1 deficiency. Mov Disord 2010; 25: 275-281.

Wang D, Pascual JM, Yang H, Engelstad K, Jhung S, Sun RP et al. Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol 2005; 57: 111-118.

Wang D, Kranz-Eble P, De Vivo DC. Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome. Hum Mutat 2000; 16: 224-231.

Veggiotti P, Teutonico F, Alfei E, Nardocci N, Zorzi G, Tagliabue A et al. Glucose transporter type 1 deficiency: ketogenic diet in three patients with atypical phenotype. Brain Dev 2010; 32: 404-408.

von Moers A, Brockmann K, Wang D, Korenke CG, Huppke P, De Vivo DC et al. EEG features of glut-1 deficiency syndrome. Epilepsia 2002; 43: 941-945.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: glut1 deficiency syndrome 1

GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles)
Search: glucose transporter type 1 deficiency syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Niklas Darin, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2012-08-21
Version: 1.1
Publication date of the Swedish version: 2012-04-03

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.