Microcephaly and glut1 deficiency

Glucose is an essential source of energy for the brain.  However, glucose is polar and cannot diffuse across the blood-brain barrier. In order to enter the cell, it must be transported across the membrane through a specific transporter.  In a family of glucose transporters, one major protein transports glucose across the blood-brain barrier:  the facilitated glucose transporter type I protein GLUT1 [2].

In a resting state, adults use roughly 20% of their whole-body glucose for brain metabolism.  In children, the demand for glucose in the brain is much higher, up to 80% of whole-body glucose utilization— or the equivalent of three to four times higher than it is in adults.  Because the demand for glucose is so high, any reduction in the supply to the developing brain will significantly impair brain function and development in a child [1].  And thus, the deficiency of the GLUT1 transporter to shunt glucose into the brain would lead to a cerebral “energy crisis” and result in the same.

 

GLUT1-Deficiency syndrome

Presentation of GLUT1 Transporter Deficiency

In 1991, a rare genetic disorder was first described where infants presented with developmental delays, microcephaly, hypotonia, motor development problems, and low cerebrospinal fluid glucose concentrations (hypoglycorrhachia) even in the presence of normal glycemic values, and seizures.  The cause of this disorder was found to be the absence of the GLUT1 transporter protein  [3, 4, 5, 6].

At birth, babies with GLUT1 deficiency syndrome may be born with a normal sized head.  However, due to the lack of glucose fueling the cerebral cells properly, the growth of the brain is slow and can result in microcephaly, developmental delays, and intellectual disability. [7]   Unfortunately, there are other GLUT1 deficiency syndrome symptoms.  Most have other pronounced neurological problems, including spasticity, ataxia, confusion, lethargy, headaches, uncontrollable muscle twitches, and difficulty with speech.  Of note, this occurs more during periods of fasting. [3]

 

ketogenic diet and microcephaly from glut1 transporter deficiency

 

Prevalence of GLUT1 Deficiency

Approximately 500 cases of GLUT1 transporter disorder have been reported since the disorder was first identified.  New estimates suggest that it may affect nearly 1 in 90,000 and that the disorder may actually be underdiagnosed since many other neurological disorders share similar symptoms.  Several conditions that were originally given other names are now recognized as mere variants of a GLUT1 deficiency include paroxysmal choreoathetosis with spasticity, paroxysmal exercise-induced dyskinesia and epilepsy, and early-onset absence epilepsy with mild intellectual disability [7]

 

Ketogenic Diet and GLUT1 Deficiency

The ketogenic diet may have the potential to be an effective treatment for GLUT1 deficiency, ketone bodies are another viable energy source for the brain.  Further, ketone bodies do not require the GLUT1 transporter protein to assist in crossing the cell membrane.

Ordinarily, utilization of ketones by the brain is minimal.  But on a ketogenic diet, ketone bodies replace glucose as fuel for the brain. The ketone bodies are then converted to acetyl-CoA by D-β-hydroxybutyrate dehydrogenase, acetoacetate-succinyl-CoA transferase, and acetoacetyl-CoA-thiolase, and then enter the Krebs cyclewithin brain mitochondria, leading to the production of adenosine triphosphate (ATP): the primary energy carrier in all of the living organisms on the planet.

 

More Evidence for the Ketogenic Diet in GLUT1 Deficiency

Some preliminary evidence suggests that the ketogenic diet will help individuals with GLUT1 Deficiency Syndrome.  One study of a family of 3 with a GLUT1 deficiency found that their seizures responded well a ketogenic diet.  It was also found that, unlike epilepsy, seizure frequency and severity of seizures worsened during fasting [3].

Because pharmaceutical treatment options are limited,  the ketogenic diet is recommended as a first-line treatment for a GLUT1 deficiency.

 

In Conclusion:

• The Glut1 defect results in low cerebrospinal fluid glucose concentrations termed hypoglycorrhachia.
• Hypoglycorrhachia results in epileptic encephalopathy and movement disorders.
• Glut1D is treatable by means of a ketogenic diet providing ketones as an alternative fuel for brain energy metabolism.
Use of the ketogenic diet as a treatment option in GLUT1 deficiency is life-altering to those who are affected.  However, according to the latest in ketogenic diet research, there are other potential life-altering applications of the ketogenic diet still worth exploring. 

 


References

1. Cremer, J. E. (1982). Substrate Utilization and Brain Development. Journal of Cerebral Blood Flow & Metabolism, 2(4), 394–407. doi:10.1038/jcbfm.1982.45]

2. Klepper, J., & Voit, T. (2002). Facilitated glucose transporter protein type 1 ( GLUT1 ) deficiency syndrome: impaired glucose transport into the brain: a review. European Journal of Pediatrics, 161(6), 295–304. doi:10.1007/s00431-002-0939-3 
]

3. Brockmann, K., Wang, D., Korenke, C. G., Von Moers, A., Ho, Y.-Y., Pascual, J. M., De Vivo, D. C. (2001). Autosomal dominant GLUT1 deficiency syndrome and familial epilepsy. Annals of Neurology, 50(4), 476–485. doi:10.1002/ana.1222 ]

4. Klepper J, Wang D, Fischbarg J, Vera JC, Jarjour IT, O’Driscoll KR, DeVivo DC. Defective glucose transport across brain tissue barriers (GLUT1): a newly recognized neurological syndrome. Neurochem Res 1999;24:587-597.]

5. Klepper J, Willemsen M, Verrips A, Guertsen E, Herrmann R, Kutzick C, Florcken A, Voit T. Autosomal dominant transmission of GLUT1-deficiency. Hum Mol Genet 200 I; 10:63-68. 
]

6. Seidner, G., Alvarez, M. G., Yeh, J.-I., O’Driscoll, K. R., Klepper, J., Stump, T. S., De Vivo, D. C. (1998). GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nature Genetics, 18(2), 188–191. doi:10.1038/ng0298-188 
]

7. Pearson, T. S., Akman, C., Hinton, V. J., Engelstad, K., & De Vivo, D. C. (2013). Phenotypic Spectrum of Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS). Current Neurology and Neuroscience Reports, 13(4). doi:10.1007/s11910-013-0342-7


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