CLN1 type
Age of onset: After 8 months of age
Causative gene: PPT1 (palmitoyl-protein thioesterase 1)
Main features: Microcephaly, epilepsy, psychomotor regression, and visual impairment appear sequentially1)
Batten Disease (Neuronal Ceroid Lipofuscinosis)
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Batten disease?
Section titled “1. What is Batten disease?”Batten disease is the common name for neuronal ceroid lipofuscinosis (NCL). It is named after British pediatrician Frederick E. Batten. It is a general term for a group of hereditary neurodegenerative diseases characterized by the accumulation of lipopigments (ceroid lipofuscin) in lysosomes, and about 30 causative genes have been identified11). Major disease types are classified based on 13 to 14 genes3).
The prevalence is estimated at about 1 per 100,000 births. The incidence in the United States is 1.6 to 2.4 per 100,000, and in Europe it is 2 to 7 per 100,0001). In Western countries, the most common type is CLN3 at 22.6%, followed by CLN2 at 21.2% and CLN1 at 19.6%1). In Japan, a national survey confirmed 27 cases.
The juvenile form caused by CLN3 mutation (Batten disease in the narrow sense) is the most common and is considered one of the most prevalent neurodegenerative diseases in childhood. Adult-onset type (ANCL; Kufs disease) accounts for about 5% of NCL mutations 5). It is the second most common cause of syndromic retinitis pigmentosa after Usher syndrome. Symptoms appear asynchronously and progress throughout life 11).
The inheritance pattern is basically autosomal recessive, but only CLN4 (DNAJC5 mutation) is autosomal dominant 3).
CLN2 type
Age of onset: 2–4 years
Causative gene: TPP1 (tripeptidyl peptidase 1)
Main features: Afebrile seizures and language delay are early signs. Only ERT (cerliponase alfa) is approved 6)
CLN3 type (juvenile type)
Age of onset: 5–10 years
Causative gene: CLN3 (battenin)
Main features: Rapid vision loss is the first symptom. Most common type.
Adult-onset (ANCL)
Age of onset: Adulthood
Causative genes: CLN4, CLN5, and others
Main features: Triad of intractable epilepsy, cognitive decline, and motor impairment. Vision is usually normal4)
Q
Is Batten disease hereditary? Should I get tested?
A
The inheritance pattern is autosomal recessive (autosomal dominant only for CLN4)3). If there is a family history, genetic counseling is recommended. Carrier testing is also possible through genetic testing.
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”Subjective Symptoms
Section titled “Subjective Symptoms”Initial symptoms vary by type. In CLN3, visual loss precedes other symptoms, while in other types, epilepsy and developmental regression are predominant.
- CLN3 (Juvenile type): Rapid central vision loss is the first sign, starting around age 6.4–6.6 years. Patients often visit an ophthalmologist between 5.5 and 8.5 years of age. It takes an average of 2.9 years from the first visit to a definitive diagnosis.
- CLN2: Onset of afebrile seizures at 2–4 years of age, with preceding language delay 6).
- CLN1: Microcephaly, epilepsy, psychomotor regression, and visual impairment appear after 8 months of age 1).
- Adult type (ANCL): The three main features are refractory epilepsy, cognitive decline, and motor impairment; vision is usually preserved 4).
- Photophobia: One of the early symptoms 11).
Q
Can a child's vision loss be due to Batten disease?
A
In CLN3 type, progressive central vision loss at ages 5–9 is the initial symptom. Retinal degeneration is confirmed by electroretinography and OCT, and unexplained progressive vision loss in children is investigated as hereditary retinal dystrophy. A diagnostic delay of an average of 2.9 years is known, making early specialist consultation important.
Clinical Findings
Section titled “Clinical Findings”Over 90% of cases show rod-cone retinal dystrophy (rod-cone IRD)11).
Initial ocular findings
Macular changes: Patchy changes and bull’s eye maculopathy are characteristic of CLN3
Electroretinogram abnormalities: Marked reduction of scotopic amplitude and decreased b:a ratio (negative-type ERG)
Photophobia: Noticed from early stages11)
Advanced-stage ocular findings
Retinitis pigmentosa: bone-spicule pigmentation, retinal arteriolar attenuation
Optic atrophy: optic disc pallor (CLN22), CLN143))
OCT findings: thinning or loss of the photoreceptor layer (CLN11), CLN77))
Characteristic findings by type are shown below.
- CLN1 (Japanese sibling cases): OCT shows marked retinal thinning1).
- CLN2: Optic atrophy, retinitis pigmentosa, and flat electroretinogram2).
- CLN5: Cone dystrophy. Visual acuity decreases to 0.1–1 in the right eye and 0.05 in the left eye9).
- CLN7 (MFSD8 mutation): OCT shows photoreceptor loss. Visual acuity progresses from 20/320 to 20/6507).
- CLN14 (KCTD7 mutation): Hypopigmented fundus and mild temporal optic disc pallor3).
- MRI in CLN3: Supratentorial cortical gray matter decreases at a rate of 4.6±0.2% per year8).
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”NCL is caused by lysosomal dysfunction due to mutations in 14 genes 3). The causative genes and age of onset for each type are shown below.
The genes and onset ages for each type are summarized.
| Type | Gene | Age of onset |
|---|---|---|
| CLN1 | PPT1 | Infancy (from 8 months) |
| CLN2 | TPP1 | Early childhood (2–4 years) |
| CLN3 | CLN3 | School age (5–10 years) |
| CLN4 | DNAJC5 | Adulthood |
| CLN5 | CLN5 | Late infantile to adult |
| CLN7 | MFSD8 | Late infantile |
| CLN14 | KCTD7 | Infancy |
The molecular functions of each type are shown below.
- CLN1 (PPT1): Deficiency of palmitoyl-protein thioesterase 1, leading to mitochondrial dysfunction and abnormal autophagy 1).
- CLN2 (TPP1): Deficiency of tripeptidyl peptidase 1. Hotspot mutations c.509-1G>A/c.622C>T are found in over 50% of cases 6).
- CLN3: Encodes battenin protein (regulates post-Golgi trafficking). The most common mutation is a 1.02 kb deletion 11).
- CLN4 (DNAJC5): Encodes presynaptic protein CSPα, with autosomal dominant inheritance 4). Aggregation of mutant CSPα leads to lipofuscin accumulation.
- CLN5: Most common in late infantile onset, adult onset is rare5).
- CLN7 (MFSD8): Lysosomal membrane transporter. Synonymous mutations can cause splicing abnormalities7).
- CLN14 (KCTD7): Encodes potassium channel tetramerization domain-containing protein 7, impairing the cullin-3-mediated ubiquitin-proteasome system3).
The inheritance pattern is generally autosomal recessive, except for CLN4 which is autosomal dominant3)4).
4. Diagnosis and Testing Methods
Section titled “4. Diagnosis and Testing Methods”Genetic testing is the mainstream approach, and molecular diagnosis is the gold standard 3). Diagnostic delay averaging over 2.9 years is a challenge, and differential diagnosis includes cone-rod dystrophy, Stargardt disease, and optic neuropathy. The misdiagnosis rate for adult-onset (ANCL) exceeds one-third 4).
The main diagnostic methods are summarized below.
| Test | Main target type | Characteristic findings |
|---|---|---|
| Enzyme activity measurement | CLN1, CLN2 | Decreased PPT1/TPP1 activity |
| Genetic testing (WES) | All types | Identification of causative mutation |
| Electron microscopy | CLN1, CLN5, etc. | GRODs, fingerprint profiles, curvilinear bodies |
| MRI | CLN3 | Cortical gray matter atrophy |
| Electroretinogram | Full-field | Markedly reduced amplitude / negative-type |
Details of each test are shown below.
- Enzyme activity measurement: PPT1 activity is measured for CLN1, and TPP1 activity for CLN21)2). In a case report of CLN2, TPP1 activity was markedly decreased at 5.4 nmol/mg protein/h (normal 390.07±118.5)2).
- Whole exome sequencing (WES): Particularly useful in cases of unknown cause3)10).
- Electron microscopy findings: GRODs (granular osmiophilic deposits) are seen in CLN1 and CLN51)5). Fingerprint profiles are characteristic of CLN2, and mixed type is characteristic of CLN3.
- MRI in CLN3: Supratentorial cortical gray matter atrophies at a rate of 4.6±0.2% per year, serving as a sensitive imaging biomarker8).
- VEP: In CLN2, giant potentials may be observed6).
- CLN2 CRS (Clinical Rating Score): Consists of four domains: motor, language, epilepsy, and vision. Used to assess treatment efficacy6).
- LysoSM-509: In CLN3, similar to Niemann-Pick disease type C, levels may be elevated (812 nmol/L, normal 1–33), so additional genetic testing is needed to differentiate between the two diseases10).
Q
What tests can diagnose it?
A
Genetic testing (including whole exome sequencing) is the mainstream approach 3). For CLN1, measurement of PPT1 enzyme activity, and for CLN2, measurement of TPP1 enzyme activity, are also useful 1)2). Electroretinography, OCT, and MRI are helpful for auxiliary diagnosis. In adult-onset cases, misdiagnosis as autoimmune encephalitis or normal pressure hydrocephalus is common 4), and it is important to include NCL in the differential diagnosis for progressive neurological and visual impairment of unknown cause.
5. Standard Treatment
Section titled “5. Standard Treatment”For many types, including CLN3, there is no curative treatment that stops or reverses symptoms, and symptomatic therapy is the mainstay.
Symptomatic Therapy
Section titled “Symptomatic Therapy”- Antiepileptic drugs: Valproic acid, carbamazepine, lamotrigine, and levetiracetam are used4).
- Dystonia: Administration of botulinum toxin type A (80–120 units) has been reported5).
- Parkinsonism: There are cases of mild improvement with levodopa/benserazide 200/50 mg three times daily9).
- Piracetam: Reported to be effective for seizures and ataxia4).
- Advanced-stage supportive care: Physical therapy, occupational therapy, speech therapy, and gastrostomy feeding are provided.
Enzyme replacement therapy (CLN2 only)
Section titled “Enzyme replacement therapy (CLN2 only)”Cerliponase alfa is the only disease-modifying therapy approved in 2017 for CLN2 (TPP1 deficiency). It is administered intraventricularly at a dose of 300 mg every two weeks6).
In a clinical trial of 24 patients, the 48-week decline in the CLN2 CRS (motor and language score) was 0.38±0.10 points, significantly suppressed compared to 2.06±0.15 points in historical controls6). In patients treated before symptom onset, the maximum CRS score was maintained at 2 years6).
It can be safely administered even in advanced-stage CLN2 cases, and there is a report that seizure frequency improved from 5.5 times/4 weeks to 3.4 times/4 weeks after administration2).
However, since cerliponase alfa distributes to the cerebrospinal fluid but does not reach the retina, visual impairment does not improve6).
Symptomatic treatment
Antiepileptic drugs: valproic acid, lamotrigine, etc.4)
Dystonia: Botulinum toxin type A (80–120 units) 5)
Supportive therapy: Physical therapy, gastrostomy feeding
Enzyme Replacement Therapy
Indication: CLN2 (TPP1 deficiency) only
Drug: Cerliponase alfa 300 mg
Administration: Intracerebroventricular infusion every 2 weeks6)
Note: No effect on the retina6)
Research stage
Gene therapy (AAV): Clinical trials ongoing for CLN3 and CLN6
Stem cell therapy: Research stage
Newborn screening: Feasibility under consideration6)
Q
Can cerliponase alfa be used for all types of Batten disease?
A
It is approved only for CLN2 (TPP1 deficiency). Because it is administered intraventricularly, it has no effect on the retina and does not improve visual impairment6). Gene therapy (AAV) clinical trials are ongoing for CLN3 and CLN6, but these are not yet established as standard treatments.
6. Pathophysiology and Detailed Mechanisms of Disease Onset
Section titled “6. Pathophysiology and Detailed Mechanisms of Disease Onset”NCLs are a group of lysosomal storage disorders, but the molecular mechanisms differ depending on the type.
- CLN1 (PPT1 deficiency): Causes abnormal autophagy and mitochondrial dysfunction 1). PPT1-deficient neurons are vulnerable to mitochondrial respiratory chain complex I inhibition 1). Fibroblasts from CLN1 patients show decreased activity of ATP synthase and complexes II, III, and IV 1).
- CLN4 (DNAJC5/CSPα): Palmitoylation-induced aggregation of mutant CSPα leads to lipofuscin accumulation 4).
- CLN5 deficiency: Causes upregulation of SNCA (α-synuclein), suggesting a pathological link to parkinsonism 9). ATP13A2 mutation (CLN12), also known as Kufor-Rakeb syndrome, shows functional overlap with CLN5 9).
- CLN7 (MFSD8): Functions as a lysosomal membrane transporter; synonymous mutations cause mRNA splicing abnormalities leading to loss of function 7).
- CLN14 (KCTD7): Impairs the cullin-3-mediated ubiquitin-proteasome system, leading to accumulation of undegraded substances 3).
- CLN3 (battenin): Encodes a protein that regulates post-Golgi trafficking, and impaired transport of phototransduction proteins causes photoreceptor degeneration 11). Similarities to BBSome (Bardet-Biedl syndrome-associated complex) function have also been noted 11).
7. Latest Research and Future Perspectives (Research-stage Reports)
Section titled “7. Latest Research and Future Perspectives (Research-stage Reports)”Gene therapy (AAV)
Section titled “Gene therapy (AAV)”Gene therapy using AAV vectors targeting CLN3 and CLN6 is in clinical trials. Since cerliponase alfa for CLN2 has shown a delay in symptom onset when administered before disease manifestation 6), the importance of presymptomatic screening and early treatment initiation is gaining attention.
Potential for Newborn Screening
Section titled “Potential for Newborn Screening”Given the effectiveness of presymptomatic treatment for CLN2, its introduction into newborn screening is being considered 6). Establishing the infrastructure to maximize the window for early diagnosis and therapeutic intervention remains a challenge.
Biomarker Research
Section titled “Biomarker Research”Hochstein et al. (2022) demonstrated in a longitudinal MRI study of CLN3 patients that supratentorial cortical gray matter volume decreases by 4.6±0.2% per year, reporting its utility as a sensitive imaging biomarker that can be used to assess treatment efficacy 8).
LysoSM-509 has been shown to have potential as a diagnostic biomarker for NCL, and it has been reported to be elevated (812 nmol/L) in CLN3 as well10). However, additional genetic testing is required to differentiate it from Niemann-Pick C disease.
Molecular correction approaches for splicing mutations
Section titled “Molecular correction approaches for splicing mutations”Elucidation of the mechanism by which synonymous mutations in MFSD8 (CLN7) cause splicing abnormalities is laying the foundation for molecular correction approaches using antisense oligonucleotides and other tools7).
Q
Are there any future treatments?
A
Gene therapy (AAV vectors) is in clinical trials for CLN3 and CLN6. Stem cell therapy is also in the research stage. For CLN2, the effectiveness of pre-symptomatic treatment has been demonstrated, and discussions on introducing newborn screening are progressing 6). Currently, there is no curative treatment other than for CLN2 type, and further research is awaited.
8. References
Section titled “8. References”- Eto K, Itagaki R, Takamura A, Eto Y, Nagata S. Clinical features of two Japanese siblings of neuronal ceroid lipofuscinosis type 1 (CLN1) complicated with Type II diabetes mellitus. Mol Genet Metab Rep. 2023;37:101019.
- Nakashima S, Hamada M, Kimura T, et al. Intraventricular cerliponase alfa treatment in a patient with advanced neuronal ceroid lipofuscinosis type 2. Intern Med. 2024;63:1807-1812.
- Zeineddin S, Matar G, Abosaif Y, Abunada M, Aldabbour B. A novel pathogenic variant in the KCTD7 gene in a patient with neuronal ceroid lipofuscinosis (CLN14): a case report and review of the literature. BMC Neurol. 2024;24:367.
- Huang H, Liao Y, Yu Y, Qin H, Wei YZ, Cao L. Adult-onset neuronal ceroid lipofuscinosis misdiagnosed as autoimmune encephalitis and normal-pressure hydrocephalus: a 10-year case report and case-based review. Medicine. 2024;103:e40248.
- Madhavi K, Alugolu R, Kandadai RM, et al. Adult-onset neuronal ceroid lipofuscinosis: CLN5 variant presenting as focal dystonia. Tremor Other Hyperkinet Mov. 2024;14:54.
- Schaefers J, van der Giessen LJ, Klees C, et al. Presymptomatic treatment of classic late-infantile neuronal ceroid lipofuscinosis with cerliponase alfa. Orphanet J Rare Dis. 2021;16:221.
- Reith M, Zeltner L, Schaferhoff K, et al. A novel, apparently silent variant in MFSD8 causes neuronal ceroid lipofuscinosis with marked intrafamilial variability. Int J Mol Sci. 2022;23:2271.
- Hochstein JN, Schulz A, Nickel M, et al. Natural history of MRI brain volumes in patients with neuronal ceroid lipofuscinosis 3: a sensitive imaging biomarker. Neuroradiology. 2022;64:1911-1912.
- Lange LM, Schell N, Tunc S, et al. Atypical parkinsonism with pathological dopamine transporter imaging in neuronal ceroid lipofuscinosis type 5. Mov Disord Clin Pract. 2022;9:1116-1119.
- Kasapkara CS, Ceylan AC, Yilmaz D, et al. CLN3-associated NCL case with a preliminary diagnosis of Niemann Pick type C. Mol Syndromol. 2023;14:30-34.
- Morda D, et al. Pediatric inherited retinal diseases: classification including NCL. Prog Retin Eye Res. 2025;109:101405.