Energy metabolism in brain differs with pediatric Huntington’s: Study
Similarities seen with glucose disorder known as GLUT-1 deficiency syndrome
The brain of people with pediatric-onset Huntington’s disease show impaired transport of blood sugar, or glucose, and low levels of a cellular machinery involved in glucose metabolism, a small study showed.
Many of these abnormalities were observed in comparisons not only with adults without Huntington’s, but also with people with adult- or juvenile-onset forms of the neurodegenerative disease.
Findings highlight that Huntington’s with childhood onset “appears clinically and biologically different” from adult-onset disease, the researchers wrote. “Such differentiation may be important not only from a therapeutic perspective but also to ensure appropriate inclusion of pediatric patients into Huntington disease clinical trials.”
The study, “GLUT-1 changes in pediatric Huntington disease brain cortex and fibroblasts: an observational case-control study,” was published in eBioMedicine.
Huntington’s with childhood onset is a very rare form of a rare disease
All forms of Huntington’s are caused by the excessive repetition of three DNA building blocks — C, A, and G — in the HTT gene. The disease usually emerges in adulthood, but a higher number of CAG repeats is linked to an earlier onset.
With juvenile-onset Huntington’s, symptoms are typically evident by around age 20. Highly expanded mutations, that is, more than about 80 CAG repeats, cause pediatric Huntington’s, where symptoms emerge in the first decade of life.
Pediatric-onset Huntington’s is a very rare and more aggressive disease form than juvenile- and adult-onset Huntington’s. The mechanisms underlying these differences still are being explored, but patients with pediatric onset often have neurodevelopmental delays or regressions, seizures, and severely reduced glucose metabolism in the brain.
Glucose is taken up by cells and broken down to produce energy. “Abnormal glucose metabolism is a hallmark of several neurodegenerative diseases [including Huntington’s] and is due, at least in part, to altered [production] of glucose transporters (GLUTs), which control glucose uptake into the brain,” the researchers wrote.
A loss of GLUTs can starve nerve cells of the energy they need to function properly.
Notably, the clinical presentation of pediatric Huntington’s overlaps with that of GLUT-1 deficiency syndrome, where the lack of the main glucose transporter, called GLUT-1, leads to a chronic glucose deficiency in the brain.
Given this overlap, its possible similar mechanisms are at play in pediatric Huntington’s and GLUT-1 deficiency, researchers in Italy and the Netherlands speculated.
The team measured the levels of glucose transporter proteins in postmortem brain tissue from 17 people. Two had pediatric Huntington’s, three had juvenile Huntington’s, and six had adult-onset Huntington’s. The remaining six samples came from adults without this disease, who served as a control group.
Significantly lower levels of a glucose transporter protein seen in frontal cortex
Results showed that GLUT-1 levels in the brain’s frontal cortex were significantly lower, by about four to five times, in pediatric-onset patients relative to all other groups. (The frontal cortex is a brain region involved in decision-making, memory, social interaction, and motor function.) Still, this deficiency was not associated with significant neurodegeneration in that region.
GLUT-1 also appeared diminished in the striatum — a brain region selectively affected by Huntington’s — of pediatric-onset patients, although group differences were not statistically significant.
Levels of another transporter, called GLUT-3, were significantly lower in both the frontal cortex and striatum of pediatric and juvenile Huntington’s patients compared with controls. People with adult-onset Huntington’s showed significantly lower GLUT-3 levels only in the frontal cortex relative to controls.
Analyses of connective tissue cells outside the brain, called fibroblasts and obtained from skin biopsies in a smaller group of patients and controls, showed that GLUT-1 and GLUT-3 levels again were significantly diminished in the pediatric Huntington’s group. These findings support the idea that HTT mutations have consequences in tissues other than the brain.
Levels of Rab11-A, a protein involved in conveying glucose transporters to the surface of nerve cells, also were significantly lower in the frontal cortex of pediatric Huntington’s patients compared with controls and adult-onset Huntington’s patients.
Brain tissue from the pediatric-onset group also had significantly lower levels of certain molecular complexes in mitochondria — a cell’s energy production centers, which utilize glucose — relative to controls.
Possibility that a special diet might help with pediatric Huntington’s disease
Altogether, the findings “highlight differences in potential biological mechanisms” between various forms of Huntington’s, the team wrote.
These conclusions, however, are limited by the very small number of pediatric-onset brain samples available for analysis, not surprising given that pediatric Huntington’s is a very rare form of an already rare disease, the researchers noted.
“More cases and more extensive examination … are required to draw any firm conclusions,” they wrote.
Still, study data could point toward possible therapeutic approaches for pediatric Huntington’s, the scientists noted.
A ketogenic diet, one high in fats and low in carbs, is commonly used to treat children with GLUT-1 deficiency and certain types of epilepsy. Such a diet, which helps shift the body’s energy source away from glucose, “could be beneficial for patients with [pediatric Huntington’s] when initiated in the early stages of the disease,” the researchers wrote.
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