Juvenile-Onset Huntington Disease Pathophysiology and Neurodevelopment: A Review

Abstract

Huntington disease is an autosomal dominant inherited brain disorder that typically becomes manifest in adulthood. Juvenile-onset Huntington disease refers to approximately 5% of patients with symptom onset before the age of 21 years. The causal factor is a pathologically expanded CAG repeat in the Huntingtin gene. Age at onset is inversely correlated with CAG repeat length. Juvenile-onset patients have distinct symptoms and signs with more severe pathology of involved brain structures in comparison with disease onset in adulthood. The aim of this review is to compare clinical and pathological features in juvenile- and adult-onset Huntington disease and to explore which processes potentially contribute to the observed differences. A specific focus is placed on molecular mechanisms of mutant huntingtin in early neurodevelopment and the interaction of a neurodegenerative disease and postnatal brain maturation. The importance of a better understanding of pathophysiological differences between juvenile- and adult-onset Huntington disease lies in development and implementation of new therapeutic strategies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: disease mechanisms; juvenile Huntington disease; neurodevelopment; pediatric Huntington disease; pediatric neurodegenerative disease.

FIG 1

Schematic illustration showing differences in juvenile‐onset Huntington disease (JHD) neuropathology in comparison with adult‐onset Huntington disease (AHD) neuropathology. More severe pathological hallmarks of JHD brains are seen in A, inset C and D: the subcortical grey matter structures and B: the frontoparietal cortex and, to a lesser extent, the cerebellum. Volume loss (−) is more pronounced in the frontoparietal cortex (red), cerebellum (green), caudate nucleus (purple), putamen (orange), nucleus accumbens (yellow), internal segment of the globus pallidus (blue), and the thalamus (pink). N‐terminal mutant huntingtin (mHTT) aggregates (▴) are more abundant in the frontal cortex, caudate nucleus, putamen, and, to a lesser extent, cerebellum of JHD brains. Exon 1 protein (●) is more abundant in the frontoparietal cortex and hippocampus (not displayed) of JHD brains. Repeat‐associated non‐ATG nuclear (RAN) proteins ($△$) are more abundant in the striatum, frontal cortex, and cerebellum of JHD brains. Somatic CAG repeat mosaicism ($\circ$) is greater in the neocortex, caudate nucleus, and putamen of JHD brains. [Color figure can be viewed at wileyonlinelibrary.com]

FIG 2

Model for potential effects of mutant huntingtin (mHTT) in the developing brain of juvenile‐onset Huntington disease (JHD) patients. Normal brain development involves overlapping processes of neurogenesis and cell differentiation (pink line), neuronal migration (green line), neural circuitry formation by dendrite branching (brown line), and synaptogenesis (first part of blue line), followed by selective synaptic pruning (second part of blue line) and myelination (yellow line). Straight lines represent physiological brain development, dotted lines potentially altered neurodevelopment due to a dosage effect of CAG repeat length or interplay with brain maturation in JHD patients. Distinct clinical characteristics in JHD patients include developmental delay, epileptic seizures, psychosis, and behavioral disorders that could relate to various defects in neurodevelopment or brain maturation (see color code of the representative lines). Note the potential bidirectional effect on synapse abundance (blue dotted lines) on developmental delay (associated with impaired prenatal synaptogenesis) and psychosis and behavioral disorders (associated with impaired postnatal synaptic pruning). [Color figure can be viewed at wileyonlinelibrary.com]