Barnat M, Capizzi M, Aparicio E, et al. Huntington's disease alters human neurodevelopment. Science. 2020;369(6505):787-793. doi:10.1126/science.aax3338
Although Huntington's disease is a late-manifesting neurodegenerative disorder, both mouse studies and neuroimaging studies of presymptomatic mutation carriers suggest that Huntington's disease might affect neurodevelopment. To determine whether this is actually the case, we examined tissue from human fetuses (13 weeks gestation) that carried the Huntington's disease mutation. These tissues showed clear abnormalities in the developing cortex, including mislocalization of mutant huntingtin and junctional complex proteins, defects in neuroprogenitor cell polarity and differentiation, abnormal ciliogenesis, and changes in mitosis and cell cycle progression. We observed the same phenomena in Huntington's disease mouse embryos, where we linked these abnormalities to defects in interkinetic nuclear migration of progenitor cells. Huntington's disease thus has a neurodevelopmental component and is not solely a degenerative disease.
van der Plas E, Langbehn DR, Conrad AL, et al. Abnormal brain development in child and adolescent carriers of mutant huntingtin. Neurology. 2019;93(10):e1021-e1030. doi:10.1212/WNL.0000000000008066
Objective: The huntingtin gene is critical for the formation and differentiation of the CNS, which raises questions about the neurodevelopmental effect of CAG expansion mutations within this gene (mHTT) that cause Huntington disease (HD). We sought to test the hypothesis that child and adolescent carriers of mHTT exhibit different brain growth compared to peers without the mutation by conducting structural MRI in youth who are at risk for HD. We also explored whether the length of CAG expansion affects brain development.
Methods: Children and adolescents (age 6-18) with a parent or grandparent diagnosed with HD underwent MRI and blinded genetic testing to confirm the presence or absence of mHTT. Seventy-five individuals were gene-expanded (GE) and 97 individuals were gene-nonexpanded (GNE). The GE group was estimated to be on average 35 years from clinical onset. Following an accelerated longitudinal design, age-related changes in brain regions were estimated.
Results: Age-related striatal volume changes differed significantly between the GE and GNE groups, with initial hypertrophy and more rapid volume decline in GE. This pattern was exaggerated with CAG expansion length for CAG > 50. A similar age-dependent group difference was observed for the globus pallidus, but not in other major regions.
Conclusion: Our results suggest that pathogenesis of HD begins with abnormal brain development. An understanding of potential neurodevelopmental features associated with mHTT may be needed for optimized implementation of preventative gene silencing therapies, such that normal aspects of neurodevelopment are preserved as neurodegeneration is forestalled.
Teams of French researchers have found cellular changes that alter cortical development in the brains of human fetuses who carry the mutant huntingtin gene (mHTT) implicated in Huntington's disease (HD).
The finding adds a new wrinkle to the puzzle of HD as many people who carry the mutation can live healthy lives for four decades or longer before the onset of symptoms.
No one knows why, but this is a common thread in other late-onset genetically-driven neurodegenerative conditions like Alzheimer's and Parkinson's disease, the researchers said. And a growing number of researchers believe that it is best to treat people with the HD mutation as early as possible.Now, findings from this study, published online July 16 in Science, beg the question: How early?
The researchers, led by Sandrine Humbert, PhD, research director of INSERM (the French National Institute for Health and Medical Research) and group leader at the Grenoble Institut des Neurosciences, and Alexandra Durr, MD, PhD, professor at Sorbonne University and team leader of the Paris Brain Institute at Pitie-Salpêtrière Hospital, had access to fetal tissue from families that terminated their pregnancy in the context of a prenatal test. The developing fetus carried the mHTT.
Other mouse and neuroimaging studies with pre-manifest mutation carriers have suggested that the mutation might affect neurodevelopment but this is the first time that scientists have looked to the human fetus to know for sure.
Study Design, Findings
Dr. Durr works with people undergoing genetic testing and counseling for Huntington's disease. Her team was able to collect cortical tissue from four HD mutation carriers when the pregnancies were terminated at around 13-weeks' gestation and tissue from four healthy controls.
This age is an opportune time to assess the tissue, the study authors noted, because at this stage the cortical neurons that project to the striatum—those that become dysfunctional and die during the course of the disease—are being born from progenitor cells at the ventricular zone.
“Thirteen weeks gestation is the time point when you need a lot of cells to be generated,” Dr. Humbert explained. “At this stage in development cells are massively cycling. The implications for the fetal brain with an HD mutation is that there is a shift to differentiate early and, as a result, you generate fewer neurons, at least at this specific time point during development.”
The scientists identified several cellular abnormalities in the developing cortex, including mislocalization of the mutant huntingtin protein and other junction proteins that keep the neuroepithelium sealed. They observed abnormal ciliogenesis and changes in mitosis and cell-cycle progression, which correlated with defects in the balance between renewal and differentiation of progenitors.ere any obvious clinical problems until mid-life? Do these early developmental changes set the stage for symptoms decades down the road? Are other brain cells compensating for the changes and it takes 40-plus years for symptoms to develop?
Dr. Humbert and her colleagues said that “the defects we observed likely render the cortico-striatal circuitry more vulnerable to the later dysfunctions characteristic of HD. The path to degeneration is complex, however, and weaves together both pathogenic and compensatory mechanisms.”
They cited a recent pair of studies in Neurology by Peg Nopoulos, MD, and her colleagues at the University of Iowa, Carver College of Medicine that looked at children who are HD mutation carriers. They showed initial striatal enlargement with hyper-connectivity between the striatum and the cerebellum. Over time, the striatum decreases and the connections weaken. Although the cerebellar connections initially may help compensate for the abnormally developed striatum, it is the loss of these connections that may ultimately lead to motor abnormalities. Again, it will be decades before any obvious motor signs develop.
“Once there are disease-modifying therapies, we know we should treat as early as possible or differently in pre-manifest compared to symptomatic stages of the disease, or it may not be sufficient,” said Dr. Humbert.
She said she is now interested in understanding how these early defects contribute to adult pathology, and how their compensation could be regulated during the silent symptom-free period. “This should give access to new molecules of interest, either as treatments or biomarkers,” she added.
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