Journal article
Abnormal brain development in child and adolescent carriers of mutant huntingtin
Neurology, Vol.93(10), pp.e1021-e1030
09/03/2019
DOI: 10.1212/WNL.0000000000008066
PMCID: PMC6745731
PMID: 31371571
Abstract
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 (
) that cause Huntington disease (HD). We sought to test the hypothesis that child and adolescent carriers of
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.
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
. 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.
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.
Our results suggest that pathogenesis of HD begins with abnormal brain development. An understanding of potential neurodevelopmental features associated with
may be needed for optimized implementation of preventative gene silencing therapies, such that normal aspects of neurodevelopment are preserved as neurodegeneration is forestalled.
Details
- Title: Subtitle
- Abnormal brain development in child and adolescent carriers of mutant huntingtin
- Creators
- Ellen van der Plas - From the Department of Psychiatry (E.v.d.P., T.R.K.), University of Iowa Hospitals & Clinics; and the Departments of Psychiatry (D.R.L., A.T., E.A.E., P.C.N.), Biostatistics (D.R.L., A.T.), and Radiology (V.A.M.) and Stead Family Department of Pediatrics (A.L.C.), University of Iowa, Iowa City. ellen-vanderplas@uiowa.eduDouglas R Langbehn - From the Department of Psychiatry (E.v.d.P., T.R.K.), University of Iowa Hospitals & Clinics; and the Departments of Psychiatry (D.R.L., A.T., E.A.E., P.C.N.), Biostatistics (D.R.L., A.T.), and Radiology (V.A.M.) and Stead Family Department of Pediatrics (A.L.C.), University of Iowa, Iowa CityAmy L Conrad - From the Department of Psychiatry (E.v.d.P., T.R.K.), University of Iowa Hospitals & Clinics; and the Departments of Psychiatry (D.R.L., A.T., E.A.E., P.C.N.), Biostatistics (D.R.L., A.T.), and Radiology (V.A.M.) and Stead Family Department of Pediatrics (A.L.C.), University of Iowa, Iowa CityTimothy R Koscik - From the Department of Psychiatry (E.v.d.P., T.R.K.), University of Iowa Hospitals & Clinics; and the Departments of Psychiatry (D.R.L., A.T., E.A.E., P.C.N.), Biostatistics (D.R.L., A.T.), and Radiology (V.A.M.) and Stead Family Department of Pediatrics (A.L.C.), University of Iowa, Iowa CityAlexander Tereshchenko - From the Department of Psychiatry (E.v.d.P., T.R.K.), University of Iowa Hospitals & Clinics; and the Departments of Psychiatry (D.R.L., A.T., E.A.E., P.C.N.), Biostatistics (D.R.L., A.T.), and Radiology (V.A.M.) and Stead Family Department of Pediatrics (A.L.C.), University of Iowa, Iowa CityEric A Epping - From the Department of Psychiatry (E.v.d.P., T.R.K.), University of Iowa Hospitals & Clinics; and the Departments of Psychiatry (D.R.L., A.T., E.A.E., P.C.N.), Biostatistics (D.R.L., A.T.), and Radiology (V.A.M.) and Stead Family Department of Pediatrics (A.L.C.), University of Iowa, Iowa CityVincent A Magnotta - From the Department of Psychiatry (E.v.d.P., T.R.K.), University of Iowa Hospitals & Clinics; and the Departments of Psychiatry (D.R.L., A.T., E.A.E., P.C.N.), Biostatistics (D.R.L., A.T.), and Radiology (V.A.M.) and Stead Family Department of Pediatrics (A.L.C.), University of Iowa, Iowa CityPeggy C Nopoulos - From the Department of Psychiatry (E.v.d.P., T.R.K.), University of Iowa Hospitals & Clinics; and the Departments of Psychiatry (D.R.L., A.T., E.A.E., P.C.N.), Biostatistics (D.R.L., A.T.), and Radiology (V.A.M.) and Stead Family Department of Pediatrics (A.L.C.), University of Iowa, Iowa City
- Resource Type
- Journal article
- Publication Details
- Neurology, Vol.93(10), pp.e1021-e1030
- DOI
- 10.1212/WNL.0000000000008066
- PMID
- 31371571
- PMCID
- PMC6745731
- NLM abbreviation
- Neurology
- ISSN
- 0028-3878
- eISSN
- 1526-632X
- Publisher
- United States
- Grant note
- T32 GM007337 / NIGMS NIH HHS K23 DE024511 / NIDCR NIH HHS
- Language
- English
- Date published
- 09/03/2019
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Radiology; Psychiatry; Pediatric Psychology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center
- Record Identifier
- 9984066393502771
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