De Vivo disease

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De Vivo disease
Autosomal dominant - en.svg
De Vivo disease has an autosomal dominant pattern of inheritance
Classification and external resources
Specialty medical genetics
OMIM 606777
GeneReviews
Orphanet 71277

De Vivo disease, more commonly known as Glut1 deficiency syndrome, is an autosomal dominant, genetic metabolic disorder associated with a deficiency of GLUT1, the protein that transports glucose across the blood brain barrier[1] also known as Glucose transporter type 1 deficiency syndrome (GLUT1-DS).

Presentation[edit]

Glut1 deficiency is characterized by an array of signs and symptoms including deceleration of head growth also known as microcephaly, mental and motor developmental delays, infantile seizures refractory to anticonvulsants, ataxia, dystonia, dysarthria, opsoclonus, spasticity, and other paroxysmal neurologic phenomena. Individuals with the disorder generally have frequent seizures (epilepsy) beginning in the first months of life. In newborns, the first sign of the disorder may be involuntary eye movements that are rapid and irregular.[2] Mothers of infants with this disorder usually have uneventful pregnancies and deliveries, with the child appearing normal and within typical birth weight and length ranges. Infants with GLUT1 deficiency syndrome have a normal head size at birth, but the growth of the brain and skull is slow, in severe cases resulting in an abnormally small head size.[2] Typically, seizures start between one and four months in 90% of cases with abnormal eye movements and apneic episodes preceding the onset of seizures in some cases.[3] Seizures usually are complex to begin with and later become more generalized. Seizure frequency is variable and a history of decreasing frequency during times of ketosis may prompt a diagnosis. Some symptoms may be present all the time (like walking difficulties), while other signs may come and go (like seizures or poor balance).[4] These findings can be clustered under three major domains: cognition, behavior and movement.[4]

Effects[edit]

The disease causes infantile seizures refractory to anticonvulsive drugs, developmental delay, acquired microcephaly and neurologic manifestations including spasticity, hypotonia, and ataxia.[5] Patients with Glut1 deficiency usually can’t learn beyond an elementary school level and often can’t live independently as adults.[6]

Genetics[edit]

Glut1 Transporter
Glut1 Transporter

De novo mutations cause Glut1 deficiency in more than 90% of patients, although it can be inherited.[7] The Glut1 protein that transports glucose across the blood brain barrier is made by the SLC2A1 gene, located on chromosome 1.[4] In Glut1 Deficiency Syndrome this gene is damaged by a mutation and the protein is not made, glucose cannot pass the blood brain barrier and by logic it can not be transported into the brain cells.[4] Having less functional GLUT1 protein reduces the amount of glucose available to brain cells, which affects brain development and function.[8] Because glucose is the primary source of fuel for the brain, patients with Glut1 Deficiency have insufficient cellular energy to permit normal brain growth and function.[4]

Diagnosis and treatment[edit]

Glut1 deficiency is diagnosed with CSF glucose value, (<2.2 mmol/L), or lowered CSF/plasma glucose ratio (<0.4), erythrocyte 3-O-methyl-d-glucose uptake assay.[3] After a confirmed low CSF glucose, genetic testing is recommended.[7]

Once diagnosed, a ketogenic diet is usually recommended as it helps to control seizures.[9] The ketogenic diet causes the body to go into ketosis, which causes a build up of ketones in the blood stream. Ketone bodies are transported across the blood-brain barrier by other means than the Glut1 protein and thus may serve as an alternative fuel for the brain when glucose is not available.[10] The ketogenic diet improves seizures for Glut1 patients but has shown a minimal effect on cognitive functions.[10] Anti-seizure medications are generally not effective, since they do not provide nourishment to the starved brain.[4] Currently, Dr. Pascual is moving forward with trials for triheptanoin, or C7 oil, to see if it will help those with Glut1 deficiency by providing an alternative fuel source to the brain.[6]

Seeing that the ketogenic diet was discovered as a way to reduce seizures long before 1991 when De Vivo was first diagnosed, it is speculated that some of the ketogentic diet's success was because the children who experienced success on the diet actually had De Vivo at a time when the disease was not yet understood. Less than 100 cases have been identified since its discovery.[2]

References[edit]

  1. ^ Todor, Arsov (2016). "Glut-1 deficiency: From Ppathophysilogy ad genetics to abroad clinical spectrum". Sanamed. 11 (2): 151–155. 
  2. ^ a b c "GLUT1 deficiency syndrome". Genetics Home Reference. Retrieved 10 October 2011. 
  3. ^ a b Wang, Pascual, Vivo. "Glucose Transporter Type 1 Deficiency Syndrome". GeneReviews. 
  4. ^ a b c d e f "Reaching for a brighter future" (PDF). Glut1 Deficiency Foundation. Retrieved 19 June 2017. 
  5. ^ Ticus I, Cano A, Villeneuve N, Milh M, Mancini J, Chabrol B (August 2008). "[GLUT-1 deficiency syndrome or De Vivo disease: a case report]". Arch Pediatr (in French). 15 (8): 1296–9. doi:10.1016/j.arcped.2008.04.024. PMID 18556184. 
  6. ^ a b "JAMA study, clinical trials offer fresh hope for kids with rare brain disease: April 2017 News Releases - UT Southwestern, Dallas, Texas". www.utsouthwestern.edu. Retrieved 2017-06-15. 
  7. ^ a b "Professional Guide" (PDF). Glut1 Deficiency Foundation. Retrieved 19 June 2017. 
  8. ^ Reference, Genetics Home. "GLUT1 deficiency syndrome". Genetics Home Reference. Retrieved 2017-06-15. 
  9. ^ De Vivo, Darryl C.; Trifiletti, Rosario R.; Jacobson, Ronald I.; Ronen, Gabriel M.; Behmand, Ramin A.; Harik, Sami I. (5 September 1991). "Defective Glucose Transport across the Blood-Brain Barrier as a Cause of Persistent Hypoglycorrhachia, Seizures, and Developmental Delay". New England Journal of Medicine. 325 (10): 703–709. doi:10.1056/NEJM199109053251006. PMID 1714544. 
  10. ^ a b Brockmann, Knut (2011-07-01). "Towards a more palatable treatment for Glut1 deficiency syndrome". Developmental Medicine & Child Neurology. 53 (7): 580–581. doi:10.1111/j.1469-8749.2011.03946.x. ISSN 1469-8749. 

External links[edit]