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Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.

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Neuronal Ceroid Lipofuscinoses Overview

Synonyms: Batten Disease, CLN Disease, NCL

, MD, , MD, , MS, , MD, , PhD, , MD, MSCS, and , PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: May 29, 2025.

Estimated reading time: 29 minutes

Summary

The purpose of this overview is to:

1.

Briefly describe the clinical characteristics of neuronal ceroid lipofuscinoses;

2.

Review the genetic causes of neuronal ceroid lipofuscinoses;

3.

Provide an evaluation strategy to identify the genetic cause of a neuronal ceroid lipofuscinosis in a proband;

4.

Review management of neuronal ceroid lipofuscinoses;

5.

Inform genetic counseling of family members of an individual with a neuronal ceroid lipofuscinosis.

1. Clinical Characteristics of Neuronal Ceroid Lipofuscinoses

Neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative disorders caused by lysosomal accumulation of cellular ceroid lipofuscin, a waste product of lipids and proteins often found in the neurons of the retina and brain. The NCLs (commonly known as Batten disease) are generally characterized by progressive brain involvement, progressive retinal dystrophy, and shortened life span. NCLs are inherited in an autosomal recessive manner except DNAJC5-related NCL (CLN4 disease), which is inherited in an autosomal dominant manner. Collectively, the NCLs are the most common inherited neurodegenerative disorders in children.

Except for CTSD-related NCL (CLN10 disease), NCLs are typically characterized by a normal neonatal course and early childhood development followed by slowing of development that progresses to loss of previously acquired skills. The onset of nervous system deterioration depends on the genetic cause of the NCL. Affected individuals have at least two, if not all, of the following clinical manifestations: vision loss, psychomotor regression, dementia, epilepsy, and movement disorders.

Although these manifestations are typically present in all individuals with an NCL, the age of onset, range of manifestations, and rate of disease progression vary by the associated gene (see Section 2).

The possibility of an NCL should be considered in a child with developmental delay, especially speech-language delays, plus any of the following:

  • Progressive vision loss
  • Epilepsy
  • Ataxia
  • Developmental regression

Additionally, an individual with epilepsy with developmental regression or ataxia should be evaluated for neurodegenerative conditions such as NCL. Although these findings might be considered possible adverse effects of anti-seizure medications (ASMs), they are not common medication side effects.

2. Genetic Causes of Neuronal Ceroid Lipofuscinoses

Genes

To date, pathogenic variants in 12 genes are confirmed to be associated with NCLs (see Table 1). Most of these genes are associated with both classic and atypical phenotypes. The more common pathogenic variants in each NCL-related gene result in a typical or classic NCL phenotype, while rarer variants may be associated with atypical phenotypes with a different age of onset and variable severity and progression. Atypical phenotypes that are attenuated (e.g., later onset and/or slower disease progression) are referred to as "protracted"; this phenomenon is postulated to be due to less deleterious pathogenic variants resulting in residual protein function.

Current NCL nomenclature incorporates the associated gene (e.g., CLN1 disease is associated with pathogenic variants in PPT1 [formerly CLN1]) and age of onset (e.g., CLN1 disease, infantile). See Table 1 for more details.

Table 1.

Neuronal Ceroid Lipofuscinoses: Genes and Phenotypes

Disorder (OMIM Entry)GeneOther DesignationsMOIAge of Onset
Classic Phenotype 1Atypical/Variant Phenotypes 1
CLN1 disease (256730)PPT1
(CLN1)		Haltia-SantavuoriARInfantile
  • Late infantile
  • Juvenile
  • Adult
CLN2 disease (204500)TPP1 2
(CLN2)		Jansky-BielschowskyARLate infantile
  • Congenital/infantile
  • Juvenile
  • Late juvenile / protracted
  • Adult
CLN3 disease (204200) CLN3 Spielmeyer-Sjogren-VogtARJuvenile
  • Protracted
  • CLN3-assoc isolated retinal degeneration
CLN4 disease (162350)DNAJC5
(CLN4)		Parry or Kufs typeADAdult
CLN5 disease (256731) CLN5 Finnish variant, late infantileARLate infantile
  • Congenital
  • Infantile
  • Juvenile
  • Protracted
  • Teenage
  • Adult
CLN6 disease (601780, 204300) CLN6 Lake Cavanagh or Indian variant, late infantileARLate infantile to juvenile
  • Protracted
  • Teenage
  • Adult Kufs type A & B
CLN7 disease (610951)MFSD8
(CLN7)		Turkish variant, late infantileARLate infantileJuvenile / late juvenile
CLN8 disease (600143, 610003) CLN8
  • Turkish variant, late infantile
  • Northern epilepsy / EPMR
ARLate infantile to juvenile
CLN10 disease (610127) CTSD ARCongenital
  • Late infantile
  • Juvenile
  • Adult
CLN11 disease (614706) GRN ARTeenage to adult
CLN13 disease (615362) CTSF ARAdult Kufs type B
CLN14 disease (611726) KCTD7 ARLate infantile

CLN = ceroid lipofuscinosis, neuronal; MOI = mode of inheritance; AR = autosomal recessive; AD = autosomal dominant; EPMR = progressive epilepsy with mental retardation

1.

Age of onset for classic and atypical/variant phenotypes are based on Gardner & Mole [2021] with updates from current literature.

2.

Some individuals with biallelic TPP1 pathogenic variants are diagnosed with the overlapping disorder spinocerebellar ataxia autosomal recessive 7.

CLN9 disease, originally erroneously associated with pathogenic variants in CLN5 [Haddad et al 2012], was reclassified in OMIM. To date, a gene has not been associated with the designation CLN9 disease.

CLN12 disease has been reported in a family segregating biallelic pathogenic variants in ATP13A2 [Bras et al 2012]. Biallelic ATP13A2 pathogenic variants have also been reported in the clinically distinct diagnoses of Kufor-Rakeb syndrome (see Neurodegeneration with Brain Iron Accumulation Disorders Overview) and spastic paraplegia 78 (OMIM 617225).

CLN Disease Phenotypes

CLN1 Disease

Presenting findings

  • Classic infantile phenotype
    • Age of onset: six to 18 months
    • Typical development in the first few months of life. Between ages six and 12 months, developmental progress slows, then acquisition of motor and cognitive skills declines along with sleep disturbances, irritability, hypotonia, acquired microcephaly, and stereotypic hand movements. Seizures begin between ages one and three years followed by progressive loss of vision.
  • Atypical (late infantile, juvenile, or adult) phenotype
    • Age of onset: 18 months to adulthood [Augustine et al 2021]
    • Later onset and slower disease progression than the infantile phenotype; however, chronology of neurodegenerative manifestations is similar, with onset of vision loss later than other neurologic manifestations.

Natural history

  • Classic infantile phenotype. By ages three to five years rapid neurodegeneration progresses to loss of motor skills (ambulation and trunk control) and cognitive decline. Children are dependent on others for care and typically require gastrostomy tube placement for feeding. Severe neurologic impairment occurs by age five years [Simonati et al 2018]. Loss of vision and light perception is a later manifestation compared to other CLN diseases. Life expectancy is between ages three and 12 years (median age: 9.5 years) [Augustine et al 2021].
  • Atypical phenotypes
    • Children with the late infantile phenotype experience severe neurologic impairment from ages six to 12 years. Life span is into the second or third decade of life (median life span reported: age 16.6 years).
    • Individuals with the juvenile phenotype may have severe neurologic impairment in the third decade; median life expectancy is age 27 years [Simonati et al 2018].
    • Life expectancy for adult-onset CLN1 disease is unknown.

Disease-modifying treatments. None approved to date; however, enzyme replacement therapy (ERT) and gene-based therapies for CLN1 disease are in development (see BDSRA Foundation, Clinical Trials & Natural History Studies).

CLN2 Disease

Presenting findings (in untreated individuals)

  • Classic late infantile phenotype
    • Age of onset: two to four years
    • Typical development until age two to four years, after which developmental progress slows with notable language delay and onset of seizures. From age four years, onset of ataxia and rapid decline in motor and language skills, cognition, and vision [Specchio et al 2020].
  • Atypical phenotype
    • Age of onset: preschool to adulthood
    • Later onset of manifestations with slower progression, often first presenting with seizures or ataxia and cerebellar atrophy or vision loss [Lourenço et al 2021]. There is clinical and molecular overlap with spinocerebellar ataxia autosomal recessive 7.

Natural history

  • Classic infantile phenotype (untreated). Rapid loss of developmental skills with loss of ambulation by ages four to five years due to myoclonus and ataxia; around age six years most gross motor function is lost, and seizures become difficult to control. Feeding and swallowing difficulties often require gastrostomy tube placement by age six years. Dependence on others markedly increases between ages seven and ten years, when complete loss of vision occurs. Life expectancy is typically between ages six and 12 years [Williams et al 2017].

Disease-modifying treatment. Targeted therapy (ERT) with cerliponase alfa has demonstrated clinically significant slowing of the decline of motor and language function, and likely prolongs life span [Schulz et al 2024] (see Targeted Therapy).

CLN3 Disease

Presenting findings

  • Classic phenotype
    • Age of onset: four to seven years
    • Onset of vision loss due to cone-rod dystrophy around age four to seven years, with rapid progression to complete blindness by around age nine to 12 years [Kuper et al 2021], often followed by or coinciding with neurobehavioral/psychiatric manifestations, cognitive decline, and sleep disturbance.
  • Protracted phenotype
    • Age of onset: juvenile to adult
    • Onset of vision loss at a similar age to the classic phenotype but with slower disease progression with a more gradual decline in cognitive and motor function, and longer expected life span compared to the classic phenotype [Cameron et al 2023]
  • CLN3-associated isolated retinal degeneration
    • Age of onset: early onset (age 7-17 years) or late onset (second to fourth decade of life)

Natural history

  • Classic phenotype. Initial presentation of vision loss due to a cone-rod dystrophy with bulls eye maculopathy leading to diagnosis of pigmentary retinopathy and referral for further evaluation [Kuper et al 2021]. Complete loss of vision typically occurs around age nine to 12 years. Many individuals have mild speech delays in early childhood recognized prior to diagnosis. School-age children have inattentiveness and issues with learning. Seizures develop around age ten years, whereas gait and motor impairment (which are due to both loss of function and involuntary movements) and cognitive decline progress over the following decade. By age 20 years most individuals are unable to ambulate and are dependent on others for care. Life expectancy is into the third decade [Ostergaard 2016]. Cardiac findings including symptomatic bradycardia and left ventricular hypertrophy [Rietdorf et al 2020, Handrup et al 2022] are typically evident after age 20 years; in one study the earliest manifestations were at age 14 years.
  • Protracted phenotype. Delayed age of onset of vision loss and other manifestations with a slower progression
  • CLN3-associated isolated retinal degeneration. No progression to other neurologic manifestations of CLN3 disease [Ku et al 2017, Smirnov et al 2021]

Disease-modifying treatments. None approved to date; however, therapies under development include (1) adeno-associated virus (AAV)-mediated gene replacement, (2) messenger RNA (mRNA)-targeted antisense oligonucleotides (ASO), and (3) small molecule therapies (see BDSRA Foundation, Clinical Trials & Natural History Studies).

CLN4 Disease

Presenting findings

  • Age of onset: adolescence to adulthood; mean age 30 years
  • Typical presentation is adult-onset behavioral changes, as well seizures, myoclonus, progressive tremor, ataxia, and dementia [Guo et al 2024]
  • Note: Retinal degeneration is typically not present.

Natural history. Not well described; however, life expectancy is shortened.

Disease-modifying treatments. None

CLN5 Disease

Presenting findings

  • Age of onset: three to 6 years; however, actual age range has not yet been established due to the low number of affected individuals reported to date
  • Psychomotor regression with clumsiness followed by progressive visual failure

Natural history

  • Progressive vision loss, dementia, and seizures develop between ages four and seven years. Life span is between ages 14 and 36 years.
  • Note: While the natural history is similar to that of CLN2 disease, the onset of CLN5 disease is slightly later and life expectancy is longer [Ge et al 2018, Zhang et al 2025].

Disease-modifying treatments. None have been approved to date; however, an adeno-associated virus (AAV) vector therapy for CLN5 disease is in development (see BDSRA Foundation, Clinical Trials & Natural History Studies).

CLN6 Disease

Presenting findings

  • Late infantile to juvenile phenotype
    • Age of onset: early childhood through early juvenile period
    • Developmental delay progressing to regression
  • Adult-onset phenotypes
    • Age of onset: early adulthood
    • Kufs Type A: progressive myoclonic epilepsy
    • Kufs Type B: dementia and a range of movement disorders

Natural history

  • Late infantile phenotype. Manifestations vary but typically progress from developmental delays to regression followed by cognitive decline and ultimately seizures. Myoclonus, sleep disturbance, and vision loss are also observed. Life span typically is late childhood or early teens [Rus et al 2022]. Note: Presentation of CLN6 disease is variable even for the classic phenotype.
  • Adult-onset phenotypes (also known as Kufs disease)
    • Kufs type A. Manifestations in addition to progressive epilepsy include cognitive decline or dementia and motor decline resulting in inability to walk and ataxia [Berkovic et al 2019].
    • Kufs type B. Manifestations include epilepsy, myoclonus, ataxia, and progressive cognitive decline, but not vision loss [Arsov et al 2011].

Disease-modifying treatments. None approved to date; however, a gene therapy for CLN6 disease is in development (see BDSRA Foundation, Clinical Trials & Natural History Studies).

CLN7 Disease

Presenting findings

  • Age of onset: two to three years
  • In one study, first concerns were gait changes (ages 2.5-4.5 years); however, often issues with speech were noted at age two years before gait changes. Seizures developed around age 3.5-4.5 years [Kayani et al 2024].

Natural history. Manifestations are similar to those of CLN2 disease. After onset of seizures, children experience a loss of skills including speech and ambulation. Life expectancy is late childhood to teenage years.

Disease-modifying treatments. None approved to date; however, a gene therapy for CLN7 disease is in development (see BDSRA Foundation, Clinical Trials & Natural History Studies).

CLN8 Disease

CLN8 disease was classically defined as two distinct phenotypes; however, recent case reports describe a phenotypic spectrum [Baltar et al 2024]. The following are the two classic phenotypes.

Presenting findings

  • Progressive epilepsy with mental retardation (EPMR), also called Northern epilepsy
    • Age of onset: five to 10 years
    • Epilepsy (generalized, tonic-clonic seizures) followed by cognitive decline
  • Late infantile phenotype
    • Age of onset: two years
    • Ataxia, speech delay, vision loss, seizures, and developmental regression. Children have a rapidly progressing course.

Disease-modifying treatments. None

CLN10 Disease

Presenting findings

  • Congenital phenotype
    • Age of onset: neonatal period (i.e., birth to age 28 days)
    • Seizures may occur prenatally; microcephaly and apnea may be present at birth.
  • Other phenotypes
    • Age of onset: variable, from early childhood to teenage years, with late infantile and juvenile presentations reported
    • May include ataxia, spasticity, speech impairment, and visual disturbance

Natural history

  • Congenital phenotype. Seizures are refractory to anti-seizure medications (ASMs); apnea / respiratory insufficiency may occur. Life expectancy is often within a few weeks of birth.
  • Other phenotypes
    • Late infantile phenotype. Movement disorders, seizures, and vision loss
    • Juvenile phenotype. Loss of motor function, ataxia, speech difficulties, cognitive decline, and vision loss
    • Life span is shortened even in children with later-onset CLN10 disease.

Disease-modifying treatments. None

CLN11 Disease

Presenting findings

  • Age of onset: mid-childhood to second or third decade
  • Visual loss, seizures, and ataxia.

Natural history. Progressive visual loss with retinal dystrophy and cataracts. Seizures, myoclonus, cerebellar ataxia, and cognitive decline. Both rapidly progressive disease courses as well as slower progression compared to other NCLs can be observed. Visual hallucinations and pyramidal signs (e.g., spasticity, hyperreflexia) have been reported.

Disease-modifying treatments. None

Other. A frontotemporal dementia (FTD)-like phenotype has been seen in heterozygotes (GRN frontotemporal dementia) and an intermediate FTD / CLN11 disease spectrum has been considered in individuals with biallelic GRN variants [Nóbrega et al 2025].

CLN13 Disease

Presenting findings

  • Age of onset: age 20-30 years
  • Cognitive and psychomotor decline

Natural history. Seizures in some. Dementia requires dependence on others for care. Life expectancy is shortened.

Disease-modifying treatments. None

CLN14 Disease

Presenting findings

  • Age of onset: early to late infancy (younger than age two years)
  • Developmental regression with progressive epilepsy. Visual loss can occur with variable rates of disease progression.

Natural history. This rare disorder, previously described as progressive myoclonic epilepsy (PME), is considered by some to be an NCL following identification of several individuals with intracellular accumulation of autofluorescent lipopigment storage material consistent with an NCL (see Table 2). PME and CLN14 disease can be distinguished by the earlier onset, more rapid progression, vision loss, and shortened life span seen in CLN14 disease. More data are necessary to elucidate the distinction between PME and CLN14 disease [Zeineddin et al 2024].

Disease-modifying treatments. None

Nomenclature

Collectively, the NCLs are now commonly referred to as Batten disease. While this name was originally used in reference to CLN3 disease, juvenile onset, use of the term has broadened in recent decades to encompass all subtypes. This single term serves as a concise, practical name for families, advocacy groups, and the scientific community to unify the NCLs. Batten disease should be considered synonymous with neuronal ceroid lipofuscinosis.

Prior to discovery of the causative genes, NCLs were clinically classified by the age of onset of the first manifestations: i.e., infantile NCL (onset 6-24 months), late infantile NCL (onset 2-4 years), juvenile NCL (onset 4-15 years), and adult NCL (onset 15-50 years) [Zhang et al 2025]. As NCL-related genes have been identified and understanding of the underlying molecular pathogenesis has increased, gene-related terminology (e.g., CLN3 disease) has largely replaced clinically defined designations, although they are occasionally still in clinical use. Kufs disease, for example, is an eponym for adult-onset NCL.

3. Evaluation Strategies to Identify the Genetic Cause of a Neuronal Ceroid Lipofuscinosis in a Proband

Establishing a specific genetic cause of a neuronal ceroid lipofuscinosis (NCL):

  • Usually involves a medical history, physical examination, family history, and genomic/genetic testing;
  • Can identify individuals with CLN2 disease, for which targeted therapy is available;
  • Can support the affected individual and their family through clarification of natural history and expected changes in function, medical needs, and life span;
  • Can aid in genetic counseling (see Section 5).

Family history. A three-generation family history should be taken, with attention to relatives with early dementia, vision loss, epilepsy, and early death and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing. Absence of a known family history does not preclude the diagnosis.

Genomic/Genetic Testing

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing can be deployed earlier and for a less specific phenotype.

  • Multigene disease association panels are often first line and can be more accessible than broader whole-exome or whole-genome testing; they often include some or all the genes listed in Table 1. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis may be considered in individuals thought to have CLN3 disease (see Table 1).
    For an introduction to CMA click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. ACMG recommends exome and genome sequencing as first- or second-tier diagnostic testing for children with intellectual disability and/or multiple congenital anomalies [Manickam et al 2021].
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Enzyme Testing

Although enzyme testing was a mainstay for diagnosis of CLN1 disease and CLN2 disease in the past, it is now primarily used following genetic/genomic testing to aid in clarifying the pathogenicity of variants of uncertain significance (VUSs).

Testing for ultrastructural abnormalities (see Table 2) on electron microscopy on blood lymphocytes, used to diagnose NCLs in the past, is no longer necessary unless assisting to aid in clarifying the pathogenicity of VUSs.

Table 2.

Neuronal Ceroid Lipofuscinoses: Ultrastructural Phenotype

DisorderGeneUltrastructural phenotype
CLN1 disease PPT1 GROD
CLN2 disease TPP1 CL
CLN3 disease CLN3 FP (CL, RL)
CLN4 disease DNAJC5 GROD
CLN5 disease CLN5 RL, CL, FP
CLN6 disease CLN6 RL, CL, FP (+ GROD for adult onset)
CLN7 disease MFSD8 RL, FP
CLN8 disease CLN8 CL-like FP, granular
CLN10 disease CTSD GROD
CLN11 disease GRN FP, CL
CLN13 disease CTSF GROD, FP
CLN14 disease KCTD7 FP, RC, CL 1

CLN = ceroid lipofuscinosis, neuronal; CL = curvilinear profiles; FP = fingerprint bodies; GROD = granular osmiophilic deposits; RL = rectilinear profiles

1.

Although individuals with biallelic KCTD7 pathogenic variants and a clinical phenotype suggestive of CLN14 disease have been reported without intracellular inclusions, variable ultrastructural phenotypes can be common in NCLs.

4. Management

Clinical practice guidelines are available for CLN1 disease [Augustine et al 2021] and CLN2 disease [Williams et al 2017, Mole et al 2021], including region-specific guidelines for CLN2 disease [Sampaio et al 2023]. The authors are not aware of any other general guidelines for management of neuronal ceroid lipofuscinoses (NCLs) or for other CLN diseases. In the absence of published guidelines, the following recommendations are based on the current literature and authors' clinical experience managing individuals with these disorders.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an NCL, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Neuronal Ceroid Lipofuscinoses: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Neurologic Neurologic eval
  • Brain MRI
  • Consider EEG if seizures are a concern.
  • For CLN3 disease: validated staging systems (CLN3SS) have been developed. 1
Eyes Ophthalmologic eval
  • To assess for retinal dystrophy, refractive errors, abnormal ocular movements, &/or strabismus
  • Perform dilated eye exam as recommended by ophthalmologist.
  • Advise on low vision services (e.g., teacher of the visually impaired).
Development (in children) Neurodevelopmental eval
  • To incl cognitive, adaptive, motor, & speech-language assessments
  • Evaluate need for early intervention programs / special education services
Musculoskeletal/ADL Orthopedics / physical medicine & rehab / PT & OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Contractures, kyphoscoliosis
  • Mobility, ADLs, & need for adaptive devices, cane, or orthoses
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) 2
Neurobehavioral/
Psychiatric 		Neuropsychiatric eval
  • For persons age >18 mo: screen for social & behavioral concerns suggestive of ASD
  • For persons age >5 years: screen for concerns incl ADHD, irritability, & anxiety
Dysarthria/
Communication 		Speech-language evalFor persons w/expressive language difficulties, consider early initiation of speech therapy incl alternative means of communication & voice banking.
Gastrointestinal/
Feeding 		Gastroenterology / nutrition / feeding team / ST eval
  • Evaluate aspiration risk & nutritional status.
  • Engage speech therapist to maintain & support swallow function.
  • Consider eval for gastrostomy tube placement in persons w/dysphagia and/or aspiration risk.
  • Assess weight & nutritional status.
  • Assess for constipation.
Incontinence Evaluate for bowel & bladder mgmt needs.
Sleep concerns Screen for sleep concerns by history (snoring, loud breathing) & refer for treatment as needed.
Cardiovascular EKG
  • EKG at baseline
  • Referral for additional studies if low heart rate compared to age norms or findings suggestive of left ventricular hypertrophy
Respiratory Screen for breathing & aspiration concerns by history & refer for further eval as needed.
Palliative care Early engagement w/palliative care team incl focus on holistic multidisciplinary care, quality of life, & supported decision makingThe essential role of the palliative care team cannot be overstated; affected persons & their family members / care providers should be encouraged to engage w/palliative care services as early in the disease course as possible.
Genetic counseling By genetics professionals 3To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of the NCL diagnosed in the proband to facilitate medical & personal decision making & family planning
Family support
& resources 		By clinicians, wider care team, & family support organizations

ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy, ST = speech therapy

1.
2.
3.

Clinical geneticist, biochemical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

4.

The Batten Disease Support, Research, and Advocacy (BDSRA) Foundation supports a growing network of clinical Centers of Excellence (CoE) for Batten Disease throughout the US. Based primarily at academic children’s hospitals, CoE provide standardized comprehensive clinical services and care in agreement with the Standards for Designation established and endorsed by the Batten Disease CoE Consortium. In addition, CoE provide peer-to-peer education, support, and mentorship.

Treatment of Manifestations

Targeted Therapy

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Targeted therapy (cerliponase alfa) is available for TPP1-related NCL (CLN2 disease). Cerliponase alfa received FDA approval in the United States in April 2017. Standard of care for children with CLN2 disease now includes this intracerebroventricular enzyme replacement therapy (ERT) infusion every two weeks [Mole et al 2021] (full text).

Table 4.

Neuronal Ceroid Lipofuscinoses: Targeted Therapy

Disorder/GeneTreatmentDosageComments
CLN2 disease (TPP1-related NCL)Cerliponase alfa (ERT) 1300 mg delivered via intracerebroventricular reservoir every 2 weeks 2
  • Significantly slows decline in motor & language function. 3
  • Appears to reduce severity of other manifestations (e.g., seizures) in many affected persons. 4
  • Presymptomatic treatment may delay disease onset. 3
  • Investigation ongoing for intravitreal use.
1.

Cerliponase alfa is a recombinant human tripeptidyl peptidase-1 (TPP1) enzyme.

2.
3.
4.

Supportive Care

Epilepsy management. Multiple seizure types, including focal, atonic, absence, tonic, and generalized tonic-clonic seizures, have been observed in NCLs.

Broad-spectrum anti-seizure medications (ASMs) including valproate, benzodiazepines (clobazam/clonazepam), lamotrigine, zonisamide,e and levetiracetam or brivaracetamare are typically preferred; however, no data support the use any one ASM.

As the NCL progresses, complete freedom from seizures is often unrealistic, but it may be achievable in earlier stages.

Sodium channel blockers (phenytoin, fosphenytoin, carbamazepine, lamotrigine, oxcarbazepine) should be used with caution as they may aggravate myoclonic and/or generalized seizures. Ketogenic diet and neuromodulation devices may be helpful, similar to responses observed in other individuals with refractory epilepsy.

Movement disorders. Spasticity, dystonia, and myoclonus can cause significant discomfort and pain, particularly in later disease stages. Baclofen, tizanidine, and diazepam can improve spasticity and, in combination with trihexyphenidyl and levodopa/carbidopa, may improve spasticity and dystonia. Botulinum toxin injections can be considered for focal spasticity and dystonia.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended. Affected individuals should be seen by a medical provider for surveillance (longitudinal monitoring of development and health) more than annually, which can be done by a primary care provider or a specialty team.

Table 5.

Neuronal Ceroid Lipofuscinoses: Recommended Follow Up

System/ConcernEvaluationComment
Neurologic Neurologic eval
  • Monitor known neurologic findings.
  • Monitor for newly developed findings such as spasticity, movement disorders, & ataxia
  • Repeat eval when there is a clinical concern.
  • EEG &/or brain MRI
  • MRI if there are movement changes
Eyes Ophthalmologic eval
  • Routinely scheduled ophthalmology follow up
  • Dilated eye exam as recommended by ophthalmologist
Development Developmental/neuropsychological eval
  • In children, repeat evals every 6-12 mos (specific intervals can depend on type of assessment, e.g., full neuropsychological eval every 12 mos, caregiver report every 6 mos).
  • In adults, necessity of eval may be case dependent.
  • Track skills longitudinally to monitor for regression/dementia.
Musculoskeletal/ADL Orthopedics / physical medicine & rehab / PT & OT eval
  • Continued follow up w/focus on function
  • Evaluate current level of mobility & ataxia.
  • Monitor need for supportive ambulation (incl wheelchair) or other adaptive technology.
Neurobehavioral/
Psychiatric 		Neuropsychiatric eval
  • Mental health follow up (anxiety, adjustment to diagnosis)
  • Behavioral health follow up for aggression, agitation, ADHD, anxiety, ASD
Dysarthria/
Communication 		Speech therapyConsider augmentative communication devices & voice banking.
Gastrointestinal/
Feeding 		Gastroenterology / nutrition / feeding team eval
  • Evaluate aspiration risk & nutritional status.
  • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk or faltering weight.
  • Monitor weight.
Incontinence Evaluate for bowel & bladder mgmt..
Sleep
  • Screen for sleep concerns by history.
  • Screen for secretion concerns by history.
Cardiovascular EKG
  • Annually, starting at age 18 yrs if not earlier 1
  • Referral for additional studies if low heart rate for age norms or any abnormalities on EKG
Respiratory Screen for concerns re breathing, mgmt of secretions, & aspiration risk by medical history.Support w/pulmonary hygiene plans & home suction machines.
Palliative Palliative care team
  • Follow up for improved QOL, pain mgmt, & sleep quality
  • Discussion of hospice if indicated
Endocrine By primary care physicianDiscuss options for menstruation mgmt in females.
Genetic counseling By genetics professionals 2Families benefit from being followed by a genetics team & informed when new treatments become available.
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:
Transition to adult care
  • Begin planning for adult medical & community support needs around age 12 yrs 3
  • Plan for transition to adult medical providers around age 18-21 yrs.
  • Connect w/state-based agencies that support persons w/intellectual & developmental disabilities to facilitate benefits access, adult waiver services, respite care, etc.

ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; QOL = quality of life

1.
2.

Clinical geneticist, biochemical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

3.

5. Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Neuronal ceroid lipofuscinoses (NCLs) caused by pathogenic variants in PPT1 (CLN1 disease), TPP1 (CLN2 disease), CLN3 (CLN3 disease), CLN5 (CLN5 disease), CLN6 (CLN6 disease), MFSD8 (CLN7 disease), CLN8 (CLN8 disease), CTSD (CLN10 disease), GRN (CLN11 disease), CTSF (CLN13 disease), and KCTD7 (CLN14 disease) are inherited in an autosomal recessive manner.

DNAJC5-related NCL (CLN4 disease) is inherited in an autosomal dominant manner.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

Sibs of a proband

  • If both parents are known to be heterozygous for an autosomal recessive NCL-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing an NCL.

Offspring of a proband. Unless an affected individual's reproductive partner also has the NCL or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in the NCL-related gene.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of the NCL-related pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the NCL-related pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with CLN4 disease have an affected parent.
  • Rarely, an individual diagnosed with CLN4 disease has the disorder as the result of a de novo DNAJC5 pathogenic variant. De novo DNAJC5 pathogenic variants have been reported; however, the proportion of individuals with CLN4 disease caused by a de novo DNAJC5 pathogenic variant is not clear due to limited parental testing data [Velinov et al 2012, Naseri et al 2021, Huang et al 2022].
  • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, de novo occurrence of a DNAJC5 pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the DNAJC5 pathogenic variant.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

  • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance is high in CLN4 disease. Reduced penetrance has not been widely reported in the literature for DNAJC5 pathogenic variants.
  • If the DNAJC5 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
  • If the parents are clinically unaffected but their genetic status is known, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CLN4 disease because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with CLN4 disease has a 50% chance of inheriting the DNAJC5 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the DNAJC5 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

Prenatal Testing and Preimplantation Genetic Testing

Once the NCL-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Chapter Notes

Acknowledgments

The authors' institutions are BDRSA Foundation Centers of Excellence and have financial support from the BDSRA Foundation USA.

Author History

Scott Demarest, MD, MSCS (2025-present)
Kristina Malik , MD (2025-present)
Andrea Miele, PhD (2025-present)
Sara E Mole, PhD; University College London (2001-2019)
Kourtney Santucci, MD (2025-present)
Leighann Sremba, MS (2025-present)
Maija Steenari, MD (2025-present)
Ineka Whiteman, PhD (2025-present)
Ruth E Williams, MD; Guy's and St Thomas' NHS Foundation Trust (2001-2019)

Revision History

  • 29 May 2025 (bp) Comprehensive update posted live
  • 11 April 2019 (ma) Chapter retired: chapter does not reflect current use of genetic testing
  • 1 August 2013 (me) Comprehensive update posted live
  • 2 March 2010 (me) Comprehensive update posted live
  • 17 May 2006 (me) Comprehensive update posted live
  • 27 January 2004 (me) Comprehensive update posted live
  • 10 October 2001 (me) Review posted live
  • 20 February 2001 (kw) Original submission

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