Huntington’s disease in the era of somatic instability, biomarkers, and targeted therapies: A narrative review

AI Summary

CAG repeat expansion in HTT causes age dependent somatic instability, driving striatal medium spiny neuron degeneration via transcriptional, proteostatic, mitochondrial, and inflammatory mechanisms.
Genetic testing for expanded HTT CAG repeat is definitive; quantitative neuroimaging and CSF biomarkers are mainly research tools and trial enrichment measures.
Current care is symptomatic multidisciplinary management; emerging disease modifying strategies include HTT lowering, somatic expansion inhibition, and gene therapies requiring precise targeting and timing.

AI Summary

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin gene (HTT), resulting in mutant huntingtin (mHTT) with toxic gain-of-function and partial loss of normal huntingtin function.

Pathophysiologically, HD involves CAG instability, age-dependent somatic expansion in vulnerable neurons, transcriptional dysregulation, proteostasis failure, mitochondrial dysfunction, excitotoxicity, and neuroinflammation, leading primarily to degeneration of striatal medium spiny neurons and later cortical involvement.

Emerging disease-modifying approaches include HTT-lowering, somatic expansion inhibition, and gene-based therapies, but efficacy depends on target selectivity, timing, delivery route, dose, and patient selection.

Basic summary

Rev Invest Clin. 2026 Jul 7;78(4):100047. doi: 10.1016/j.ric.2026.100047. Online ahead of print.

ABSTRACT

Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin gene (HTT), resulting in mutant huntingtin (mHTT) with toxic gain-of-function and partial loss of normal huntingtin function. This narrative review summarizes recent advances in genetics, pathophysiology, clinical features, diagnostic assessment, biomarkers, and therapeutic development. Genetic testing demonstrating an expanded HTT CAG repeat is the definitive diagnostic test and should be interpreted with genetic counseling and attention to allele categories. Pathophysiologically, HD involves CAG instability, age-dependent somatic expansion in vulnerable neurons, transcriptional dysregulation, proteostasis failure, mitochondrial dysfunction, excitotoxicity, and neuroinflammation, leading primarily to degeneration of striatal medium spiny neurons and later cortical involvement. Clinically, HD can begin from juvenile to late-adult life and manifests with motor, cognitive, psychiatric, and behavioral symptoms that evolve from premanifest biological change to functional decline. Current clinical care relies on symptom-directed treatment, whereas quantitative neuroimaging, cerebrospinal fluid biomarkers are mainly used for research and trial enrichment. Symptomatic management includes vesicular monoamine transporter type 2 inhibitors, antipsychotics, rehabilitation, nutritional support, and multidisciplinary care. Emerging disease-modifying approaches include HTT-lowering, somatic expansion inhibition, and gene-based therapies, but efficacy depends on target selectivity, timing, delivery route, dose, and patient selection.

PMID:42413168 | DOI:10.1016/j.ric.2026.100047

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