Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the IT15 gene (HTT gene, chromosome 4p16.3). The CAG repeat produces a polyglutamine chain, resulting in mutant huntingtin protein (mHTT).
mHTT tends to aggregate, causing transcriptional and translational impairment, excitotoxicity, reduced axonal transport, and mitochondrial and synaptic dysfunction, leading to neuronal death. Early loss of medium spiny neurons in the striatum results in characteristic hyperkinetic movement disorders.
The relationship between CAG repeat number and phenotype is shown in the table below.
| CAG repeat number | Phenotype |
|---|---|
| ≤35 | Normal |
| 36–39 | Incomplete penetrance |
| ≥40 times | Complete penetrance (onset) |
Epidemiologically, it is estimated at 5.7 per 100,000 people in Europe and North America, 0.4 in Asia, and about 2.1 worldwide. Onset typically occurs in the 40s to 50s, but juvenile onset (under 21) also exists and is associated with paternal inheritance.
Overview of ocular symptoms: saccadic abnormalities, pursuit movement disorders, fixation abnormalities, and retinal thinning are the main findings. Ocular changes can appear in the early stages of HD. Curative treatment has not been established, and clinical trials of HTT-lowering therapy are ongoing.
Ocular changes can be observed in the early stages of HD, and in some cases even in the pre-symptomatic stage. Abnormal saccadic latency has been reported as an indicator that can distinguish between patients with motor symptoms and pre-symptomatic individuals.
HD patients themselves rarely notice abnormal eye movements. The following are symptoms that may be perceived.
Saccadic Abnormalities
Vertical saccade impairment: More prominent than horizontal. Presents with decreased velocity, reduced amplitude, and prolonged latency.
Voluntary saccade initiation difficulty: Difficulty in eye movement in response to commands. Reflexive saccades are relatively preserved.
“Visual grasp” reflex: Difficulty suppressing reflexive saccades, leading to a phenomenon similar to the visual grasp reflex.
Fixation and Pursuit Abnormalities
Fixation abnormality: Irregular oscillations occur when focusing on a target.
Smooth pursuit impairment: Inability to smoothly track a moving object. Compensatory jerky eye movements appear.
Frequency: Abnormalities in fixation and smooth pursuit are observed in the majority of HD patients.
Retinal thinning
Temporal RNFL thinning: Reported in multiple OCT studies. HD patients 62.3 μm vs control group 69.8 μm (significant difference).
Correlation with disease duration: Longer disease duration is significantly correlated with temporal RNFL thinning.
Macular choroidal thickness: Some studies have found only a significant decrease in macular choroidal thickness, while the effect on RNFL varies between studies.
In a study of 50 patients, 62% showed slowing of vertical saccades, 56% showed hypometric and reduced vertical saccade range, and 89% showed prolonged latency.
Vertical saccade abnormalities are more pronounced than horizontal saccades. Studies have confirmed prolonged latency of vertical saccades in 89% of patients, and slowing and amplitude reduction are also more prominent in the vertical direction than in the horizontal direction.
The cause of HD is an expansion of CAG repeats in the IT15 (HTT) gene. The inheritance pattern is autosomal dominant, with a 50% probability of passing the gene to offspring.
A definitive diagnosis of HD is made by genetic testing. Eye movement testing is used for evaluation and monitoring of HD progression.
The following table summarizes the UHDRS oculomotor assessment items.
| Assessment item | Assessment direction |
|---|---|
| Ocular pursuit | Horizontal and vertical |
| Saccade initiation | Horizontal and vertical |
| Saccade velocity | Horizontal and vertical |
There is currently no disease-modifying drug for HD. Treatment is mainly symptomatic.
HD causes region-specific neuronal loss in the cortex and striatum. The mechanisms of saccade abnormalities are as follows.
This selective pathway disruption explains saccade initiation abnormalities, pursuit movement abnormalities, and fixation abnormalities together.
Two hypotheses have been proposed for the mechanism of retinal thinning.
mHTT aggregation causes neuronal death through transcriptional/translational impairment, proteostasis abnormalities, excitotoxicity, reduced axonal transport, decreased neurotrophic factor support, and mitochondrial/synaptic dysfunction. Astrocytic gliosis in the striatum increases with pathological grade. Astrocyte Kir4.1 ion channel dysfunction has also been shown to contribute to neuronal dysfunction in HD model mice.
Saccade latency is promising as an objective indicator of disease progression. The test-retest ICC ranges from 0.55 to 0.87 (moderate to high reliability), and reports indicate that it can distinguish patients with motor symptoms from pre-symptomatic individuals. A 3-year follow-up showed that latency increases by 24 ms/year.
Macular retinal thickness: A statistically significant regression equation has been confirmed between mean macular retinal thickness and UHDRS score. However, further research is needed to verify sensitivity and specificity.
Korpela S et al. reported that CSF GFAP (glial fibrillary acidic protein) in HD is useful as a biomarker of astrocyte damage 1). The CSF GFAP concentration in the manifest HD group (ManHD) was 424 ng/L (SD 253), which was higher compared to the premanifest group (PreHD) 266 ng/L (SD 92.4) and the control group 208 ng/L (SD 83.7). A strong correlation between GFAP and cUHDRS was confirmed (r = −0.77, p < 0.001), which remained significant after DBS correction (p = 0.003). The correlation between GFAP and 5-year onset risk in premanifest carriers was r = 0.70 (p = 0.008).
NfL (neurofilament light chain) is positioned as the most promising CSF biomarker associated with onset timing and clinical severity1). On the other hand, CSF Aβ42 is considered to have limited usefulness as a biomarker1).
In the R6/2 mouse model, ultrastructural changes in the optic nerve, such as lamellar separation of myelin sheaths, irregular demyelinated axons, and the presence of myelinoid bodies, have been confirmed by electron microscopy. The myelin sheath thickness of the optic nerve in model mice is significantly reduced compared to wild-type, suggesting that optic nerve degeneration may constitute part of the pathology of HD.
Clinical trials of HTT-lowering therapies (antisense oligonucleotides and gene silencing) that suppress the production of mHTT are ongoing and are considered the most promising candidates for disease-modifying treatment.
Saccade latency has confirmed test reliability (ICC 0.55–0.87), with changes of 24 ms/year reported over three years. A significant regression equation has also been shown between macular retinal thickness and UHDRS scores. However, further research is needed to establish it as a clinical biomarker.
