| Category | CLN1 disease summary | Key details / numbers | Evidence |
|---|---|---|---|
| Disease / identifiers | Neuronal ceroid lipofuscinosis 1; CLN1 disease; infantile neuronal ceroid lipofuscinosis (INCL); infantile Batten disease | MONDO: **MONDO:0009744**; Orphanet: **228329**. OMIM was **not explicitly available in retrieved evidence**. | (pqac-00000000, pqac-00000003, pqac-00000005) |
| Causal gene / protein | **PPT1** encodes palmitoyl-protein thioesterase 1, a lysosomal depalmitoylating enzyme | Open Targets shows strongest disease-target association for PPT1 in neuronal ceroid lipofuscinosis 1. PPT1 removes palmitate from S-palmitoylated proteins to enable lysosomal degradation. | (pqac-00000000, pqac-00000004, pqac-00000017) |
| Inheritance | **Autosomal recessive** Mendelian disorder | Usually caused by **biallelic loss-of-function** PPT1 variants; most common presentation is infantile CLN1. | (pqac-00000004, pqac-00000003, pqac-00000018) |
| Variant notes | Recurrent severe alleles are repeatedly cited in older molecular literature | **R122W (c.364A>T)** and **R151X (c.451C>T)** each account for about **20%** of abnormal CLN1 alleles in the cited source; truncating variants predict near-total loss of activity. | (pqac-00000002, pqac-00000017) |
| Typical onset | Early childhood, classically infantile | Onset commonly **6–18 months** for seizures/loss of motor function; broader cited range **6–24 months**; developmental regression often evident by **~18 months**. | (pqac-00000016, pqac-00000015, pqac-00000018) |
| Core clinical features | Rapidly progressive neurodegeneration with visual, motor, cognitive, and seizure phenotype | Psychomotor regression, hypotonia/decreased tone, ataxia, myoclonus, epilepsy/seizures, loss of speech, visual failure, progressive brain atrophy/microcephaly, feeding difficulty; by **24 months** many children become blind and lose cognitive/active motor skills. | (pqac-00000016, pqac-00000015, pqac-00000017) |
| Natural history / progression | Severe, progressive, usually fatal pediatric disease | Visual loss often appears around **12 months**; by **2 years** blindness with optic atrophy/macular-retinal changes may be present; disease progresses to spasticity/vegetative state in severe forms. | (pqac-00000014, pqac-00000017) |
| Survival / prognosis | Poor without curative therapy | Death usually reported between **9 and 13 years** in one review; another review states affected children “seldom survive past early childhood”; mouse-model review cites fatal outcome by **9–13 years**. | (pqac-00000016, pqac-00000015, pqac-00000004) |
| Epidemiology | Rare disease; most retrieved numbers are for **NCL overall**, not CLN1-specific | NCL incidence estimates: **~2/100,000 live births** overall; **1.6–2.4/100,000** (USA), **2–2.5/100,000** (Denmark), **2.2/100,000** (Sweden), **3.9/100,000** (Norway), **4.8/100,000** (Finland), **7/100,000** (Iceland); one Italy estimate **0.98/100,000** and overall range **1–2.5/100,000**. | (pqac-00000018, pqac-00000016, pqac-00000014) |
| Key diagnostic modalities | Enzymatic, ultrastructural, neurophysiologic, imaging, and molecular testing | **Low/absent PPT1 enzyme activity** is a hallmark; ultrastructure shows **GRODs** (granular osmiophilic deposits); literature and trial protocols reference **genetic testing**, **MRI**, **EEG**, **ERG**, **VEP**, skin biopsy, and TEM monitoring. | (pqac-00000002, pqac-00000020, pqac-00000022) |
| Mechanistic highlight 2024: lysosomal nutrient sensing / mTORC1 | PPT1 loss disrupts lysosomal nutrient-sensing scaffold and drives abnormal mTORC1 activation with autophagy impairment | Misrouting of **v-ATPase** and **Lamtor1** from lysosomal membrane; increased **pS6K1** and **p4E-BP1** in Cln1−/− cortex and patient lymphoblasts; PI3K/Akt inhibition suppressed mTORC1 activation, restored autophagy, and improved neuropathology in mice. | (pqac-00000011, pqac-00000012) |
| Mechanistic highlight 2025: NPC1 / OSBP / cholesterol axis | PPT1 deficiency misroutes **NPC1**, causing lysosomal cholesterol accumulation and cholesterol-mediated mTORC1 hyperactivation | Proposed chain: **PPT1 loss → persistent NPC1 palmitoylation/mistrafficking → lysosomal cholesterol retention → OSBP/VAPA/VAPB-facilitated mTORC1 activation → autophagy inhibition → neurodegeneration**; OSBP inhibitor **OSW1** reduced CD68/GFAP/pS6K1/p4E-BP1 and improved neuron counts/cortical thickness in mice. | (pqac-00000008, pqac-00000009, pqac-00000010, pqac-00000026) |
| Mechanistic highlight 2024: synaptic substrate AKAP5 | Excessive synaptic palmitoylation links synaptic dysfunction to neuroinflammatory signaling | Palmitoyl-proteomic screening identified **AKAP5** as excessively palmitoylated in Ppt1−/− synapses; **NFAT** signaling was sensitized; **FK506/tacrolimus** modestly improved neuroinflammation in mice. | (pqac-00000006) |
| Mechanistic highlight 2024: synaptic substrate GABAAR | PPT1 regulates inhibitory circuitry via depalmitoylation of GABAAR α1 | **GABAAR α1** identified as PPT1 substrate; PPT1 depalmitoylates **Cys260** and binds **Cys165/Cys179**; PPT1 or binding-site mutations enhanced inhibitory transmission, altered CA1 oscillations/phase coupling, and impaired learning/memory in young mice. | (pqac-00000006) |
| 2023 therapeutic development: HSPC gene therapy | Hematopoietic stem/progenitor cell gene therapy showed strong preclinical benefit in CLN1 mouse model | Wild-type HSPC transplant gave partial benefit; **lentiviral hPPT1-overexpressing HSPCs** improved efficacy; **ICV** delivery transiently ameliorated disease; combined **IV + ICV** transduced HSPC transplantation gave the most robust benefit in pre-symptomatic and symptomatic animals. | (pqac-00000004) |
| Stem-cell trials | Early human stem-cell transplantation studies reached phase 1 / phase Ib but remained limited | **NCT00337636**: Phase 1, HuCNS-SC surgical implantation + 12 months immunosuppression, **6 enrolled**, CLN1/CLN2. **NCT01238315**: Phase Ib intracerebral HuCNS-SC, **withdrawn** for lack of accrual, **0 enrolled**. | (pqac-00000019, pqac-00000021) |
| Small-molecule / repurposing trial | Cysteamine-based therapy explored clinically in CLN1 | **NCT00028262**: Phase 4 single-group trial of **Cystagon (cysteamine bitartrate)** + **N-acetylcysteine**; **10 enrolled** (9 evaluable in summary), oral Cystagon every 6 h; primary outcome tracked **GRODs** by TEM over long-term follow-up; reported no major safety signal aside from one transient mild GI event; preliminary slowing of some progression parameters but not disease arrest. | (pqac-00000020, pqac-00000022) |
| Therapeutic status overall | No established curative therapy for CLN1 in retrieved evidence | Reviews describe preclinical ERT, gene therapy, immunomodulation, stem-cell approaches, and symptomatic care; unlike CLN2, no approved disease-specific therapy for CLN1 was documented in the retrieved 2023–2025 evidence set. | (pqac-00000001, pqac-00000003, pqac-00000013) |


*Table: This table condenses the most actionable disease-knowledge-base facts for CLN1 disease, including identifiers, genetics, natural history, diagnostics, epidemiology, and recent mechanistic and therapeutic developments. It is designed to support rapid curation with citation-linked evidence.*