Update on Genetic Chorea

Abstract

Hereditary choreas are a clinically and genetically heterogeneous group of monogenic disorders in which chorea constitutes the core or an early-dominant feature. These conditions result from various genetic mutations affecting the structures and pathways involved in movement control, primarily the caudate and putamen, ultimately impairing the basal ganglia circuits involved in the regulation of movement, cognition, and behavior. This review focuses on the main forms of hereditary choreas, including Huntington's disease, neuroacanthocytosis syndromes, Huntington's disease phenocopies, benign hereditary chorea, and other less common genetic disorders presenting with chorea. We discuss the clinical, genetic, and pathophysiological features of each condition, alongside key aspects of phenomenology, examination, and complementary tests-including laboratory findings-to guide phenotype-driven genetic testing. We detail the characteristic features of key disorders while also highlighting less common but emerging conditions. This review aims to assist neurologists in recognizing and diagnosing hereditary choreas efficiently, including guidance on the selection of appropriate genetic tests, thereby reducing diagnostic delays, informing accurate counseling, and facilitating access to disease-specific interventions and clinical trials.

Keywords: Huntington disease‐like; Huntington's disease; benign hereditary chorea; hereditary chorea; neuroacanthocytosis.

FIGURE 1

MRI images from patients with genetic choreas (A–I). (A) T1‐weighted MRI of a patient with early‐stage Huntington's disease showing mild caudate atrophy (arrows). (B) T2‐weighted MRI of a patient with the Westphal variant of Huntington's disease showing characteristic hyperintensity in the putamen associated with caudate atrophy. (C) FLAIR MRI demonstrating caudate atrophy in a patient with neuroacanthocytosis due to a VPS13A mutation. (D, E) Coronal T1‐weighted and axial T2‐weighted images showing asymmetric atrophy, predominantly in the right frontal lobe, in a patient with a C9orf72 mutation, chorea, and frontotemporal cognitive decline. (F) FLAIR MRI of a patient with SCA17 presenting with ataxia, parkinsonism, and chorea, showing a right putaminal rim and cerebellar and caudate atrophy. (G–I) MRI of a patient with DRPLA: (G) T1‐weighted image showing hypointensity in the pons and cerebellar atrophy, (H) FLAIR image showing characteristic white matter hyperintensities, and (I) FLAIR image showing hyperintensity in the superior cerebellar peduncle and brainstem pathways.

FIGURE 2

Diagnostic approach to adult‐onset chorea. Stepwise diagnostic algorithm for patients presenting with chorea. The initial evaluation focuses on excluding acquired causes through clinical history, laboratory studies, neuroimaging, and cerebrospinal fluid analysis when appropriate. In chronic or progressive cases, a genetic etiology should be suspected [(A) Step 1—Differential diagnosis of adult‐onset chorea]. Targeted genetic testing is recommended in the presence of specific diagnostic clues (e.g., acanthocytosis, MRI findings, systemic involvement). In the absence of such clues, broader approaches including repeat expansion testing and phenotype‐guided next‐generation sequencing panels should be considered [(B) Step 2—Work‐up of suspected genetic chorea]. See Tables 1, 3, and 5 for detailed clinical and ancillary test correlations.