| Phenotype/biomarker | HPO term(s) | Typical onset window | Frequency/quant | Notes (severity/progression) | Evidence source + URL | Citation ID |
|---|---|---|---|---|---|---|
| Language delay / regression | HP:0000750 Delayed speech and language development; HP:0002376 Developmental regression | Usually 2–4 years in classic CLN2; later in atypical cases | Common early hallmark; clinicians should suspect CLN2 in children age 2–4 with language delay and epilepsy | Early presenting feature in classic disease; progressive loss contributes to ML scale decline; atypical cohort median first symptom age 5.9 years, diagnosis 10.8 years | Sampaio et al. 2023, https://doi.org/10.1055/s-0043-1761434; Wibbeler et al. 2021, https://doi.org/10.1177/0883073820977997 | (pqac-00000008, pqac-00000004) |
| Epilepsy / seizures | HP:0001250 Seizure; HP:0002123 Generalized myoclonic seizure | Typically 2–4 years | Common early hallmark; natural history text notes symptoms typically start at 2–4 years | Major driver of presentation; progressive epilepsy with later myoclonic predominance described in CLN2; key clue for early diagnosis | Sampaio et al. 2023, https://doi.org/10.1055/s-0043-1761434; NCT03862274, https://clinicaltrials.gov/study/NCT03862274 | (pqac-00000008, pqac-00000025) |
| Ataxia | HP:0001251 Ataxia | Median onset about 4 years in treated movement-disorder cohort | 89% | Near-universal movement phenotype; part of stereotyped progression, often initial movement disorder | Spaull et al. 2024, https://doi.org/10.1212/WNL.0000000000209615 | (pqac-00000011) |
| Myoclonus | HP:0001336 Myoclonus | Median onset about 5 years | 83% | Near-universal; early/core movement disorder; often follows ataxia in stereotyped progression | Spaull et al. 2024, https://doi.org/10.1212/WNL.0000000000209615 | (pqac-00000011) |
| Spasticity | HP:0001257 Spasticity | Median onset about 7.5 years | 61% | Later-emerging pyramidal feature; in severity subsample 7/15 affected (4 minimal, 1 mild, 2 moderate) | Spaull et al. 2024, https://doi.org/10.1212/WNL.0000000000209615 | (pqac-00000011) |
| Dystonia | HP:0001332 Dystonia | Median onset about 8 years | 61% | Later hyperkinetic feature; in severity subsample 9/15 affected (2 minimal, 2 mild, 5 moderate) | Spaull et al. 2024, https://doi.org/10.1212/WNL.0000000000209615 | (pqac-00000011) |
| Hypokinesia / bradykinetic features | HP:0001262 Hypokinesia | Median onset about 10 years | 44% | Late-stage feature; progression pattern reported as initial ataxia/myoclonus, then hyperkinesia/spasticity, then hypokinesia | Spaull et al. 2024, https://doi.org/10.1212/WNL.0000000000209615 | (pqac-00000011) |
| Multiple movement-disorder phenotypes | HP:0004305 Abnormality of movement | Childhood, after initial neurologic onset | Median 4 distinct phenotypes per child (range 0–7) | Noncanonical movement disorders common despite ERT; UBDRS physical progression slowed from 1.45 points/month before diagnosis to 0.44 points/month on treatment (p=0.019) | Spaull et al. 2024, https://doi.org/10.1212/WNL.0000000000209615 | (pqac-00000011) |
| Motor decline / regression | HP:0001270 Motor delay; HP:0002376 Developmental regression | Symptoms typically start 2–4 years; by ~6 years many children cannot walk or sit unsupported | Natural history text: many children lose unsupported sitting/walking by ~6 years | Rapidly progressive in classic disease; central outcome domain in CLN2 motor-language scales and ERT studies | NCT03862274, https://clinicaltrials.gov/study/NCT03862274; Sampaio et al. 2023, https://doi.org/10.1055/s-0043-1761434 | (pqac-00000025, pqac-00000008) |
| Visual decline / retinal dystrophy / blindness | HP:0000556 Retinal dystrophy; HP:0000610 Abnormality of the retina; HP:0000618 Blindness | Vision loss often begins after age 3; visual deterioration by ~7 years in classic disease | Common and progressive; natural history text notes blindness by mid-childhood in many patients | Bilateral symmetric outer retinal degeneration; ICV cerliponase slows neurologic decline but does not prevent retinopathy | Wawrzynski et al. 2024, https://doi.org/10.1038/s41433-023-02859-4; Wibbeler et al. 2021, https://doi.org/10.1177/0883073820977997 | (pqac-00000015, pqac-00000004) |
| Paracentral macular volume (PMV) loss on OCT | HP:0007703 Abnormality of retinal morphology | Retinal degeneration detectable in childhood; more active in younger patients in trial | Mean baseline PMV 1.28 mm3 treated eye, 1.27 mm3 control eye; among 3 progressors, PMV decline 0.168 mm3/year treated vs 0.254 mm3/year untreated | In first-in-human intravitreal rhTPP1 study, 3 youngest patients had bilateral thinning; treated eyes declined more slowly; significant treated-vs-untreated differences (p=0.015, p=0.022, p=0.0050 in individual cases) | Wawrzynski et al. 2024, https://doi.org/10.1038/s41433-023-02859-4 | (pqac-00000015, pqac-00000016, pqac-00000017) |
| Reduced pRNFL thickness on OCT | HP:0030627 Abnormal retinal nerve fiber layer morphology | Early childhood neurodegeneration; mean age at exam 6.90 years | Mean global pRNFL 77.02 μm vs normative 106.45 μm (p<0.0001) | Progressive thinning over time in most patients; correlated with age (rs=-0.557), Weill Cornell LINCL scale (rs=0.849), and Hamburg ML scale (rs=0.833) | Gkalapis et al. 2024, https://doi.org/10.2147/EB.S473408 | (pqac-00000009) |
| Quality-of-life / functional decline captured by ML scales | HP:0033667 Impaired mobility; HP:0002476 Global developmental delay | Progressive from early childhood | Quantified longitudinally by CLN2 Clinical Rating Scale motor and language domains | Useful composite severity biomarker in trials and natural history; stabilization on treatment is a key endpoint in classic and atypical cohorts | NCT03862274, https://clinicaltrials.gov/study/NCT03862274; Wibbeler et al. 2021, https://doi.org/10.1177/0883073820977997 | (pqac-00000025, pqac-00000004) |


*Table: This table summarizes major clinical manifestations and measurable biomarkers reported for CLN2 disease, including suggested HPO terms, approximate onset windows, quantitative frequencies where available, and progression notes. It is useful for structuring phenotype annotations and selecting clinically meaningful monitoring features for a disease knowledge base.*