Objective: To describe the clinical and phenotypic features of patients with concurrent Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS), and to examine HD patients with ALS-affected first- or second-degree relatives.

Background: HD and ALS are progressive neurodegenerative disorders with distinct but occasionally overlapping clinical features [1-2]. HD is characterized by chorea, dystonia, cognitive decline, and psychiatric symptoms, while ALS manifests as progressive upper and lower motor neuron degeneration. Rare cases of coexistent HD and ALS have been documented [3-7]. The neuropathological implications of this overlap remain incompletely understood.

Method: A retrospective case series was performed at the UPMC HDSA Center of Excellence and ALS Clinic over five years. Cases of genetically confirmed HD and EMG-confirmed ALS were identified. HD patients with first- or second-degree relatives with ALS were also reviewed.

Results: Three cases of concomitant HD and EMG-confirmed ALS were identified; all had older-onset HD (ages 51–76). Two had reduced penetrance CAG repeats (38–39), one had full penetrance (CAG 46). ALS onset phenotypes differed across all three cases: limb, axial, and bulbar. Mean survival from HD onset was 2.5 years; mean survival from ALS onset was 12.6 months. ALS symptoms were initially misattributed to HD in all three cases, causing diagnostic delays of 3–12 months. Five HD patients with relatives with ALS were also identified; all five demonstrated older-onset HD.

Conclusion: We describe three cases of concomitant HD and ALS over a 5-year period, all featuring older-onset HD and varied ALS phenotypes. Several studies have shown that MND risk is not elevated in patients with pathologic HTT repeats [5]. If purely coincidental, co-occurrence would be predicted at 2–6 cases per billion [4]. Our experience suggests concurrent HD and ALS may be more prevalent than recognized. Clinicians should maintain a low threshold to consider ALS in HD patients with atypical or accelerated motor decline. Further clinical and molecular studies are needed to clarify shared pathophysiologic mechanisms and whether older-onset HD confers elevated ALS risk.

References: References
1. Jiang A, Handley RR, Lehnert K, Snell RG. From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research. Int J Mol Sci. 2023 Aug 21;24(16):13021.
2. Sharma R, Khan Z, Mehan S, Das Gupta G, Narula AS. Unraveling the multifaceted insights into amyotrophic lateral sclerosis: Genetic underpinnings, pathogenesis, and therapeutic horizons. Mutat Res Rev Mutat Res. 2024 Jul-Dec;794
3. Takahashi R, Furuta M, Nagashima K, Ikeda Y. Concurrent Amyotrophic Lateral Sclerosis and Huntington’s Disease. Intern Med. 2025 Jan 15;64(2):297-300.
4. Tada M, Coon EA, Osmand AP, Kirby PA, Martin W, Wieler M, et al. Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study. Acta Neuropathol. 2012;124(5):749-760.
5. Roos AK, Stenvall E, Skelton Kockum E, Åman Grönlund K, Alstermark H, Wuolikainen A, et al. Small striatal huntingtin inclusions in patients with motor neuron disease with reduced penetrance and intermediate HTT gene expansions. Hum Mol Genet. 2024;33(22):1966-1974.
6. Bozovic, I., Gluscevic, S., Kezic, I. et al. Bulbar-onset amyotrophic lateral sclerosis in a patient with genetically confirmed Huntington’s disease: a case study. Egypt J Neurol Psychiatry Neurosurg 60, 23 (2024).
7. Fung WLA, Mah H, Gibbons C. Co-occurrence of amyotrophic lateral sclerosis and huntington’s disease – a systematic review. Journal of Neurology, Neurosurgery & Psychiatry 2018;89:A43.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-phenotypic-features-of-concurrent-huntingtons-disease-and-amyotrophic-lateral-sclerosis-a-case-series/