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Neuronal Ceroid-Lipofuscinoses

Synonyms: Batten Disease. Includes: CLN1 Disease, CLN2 Disease, CLN3 Disease, CLN4 Disease, CLN5 Disease, CLN6 Disease, CLN7 Disease, CLN8 Disease, CLN10 Disease, CLN11 Disease, CLN12 Disease, CLN13 Disease, CLN14 Disease

, PhD and , MD.

Author Information
, PhD
MRC Laboratory for Molecular Cell Biology and UCL Institute of Child Health
University College London
London, United Kingdom
, MD
Consultant Paediatric Neurologist, Department of Paediatric Neurology
The Evelina Children's Hospital
Guy’s and St Thomas’ NHS Foundation Trust
London, United Kingdom

Initial Posting: ; Last Update: August 1, 2013.

Summary

Disease characteristics. The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by mutations in PPT1 but with differing age of onset.

The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin):

  • CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage.
  • CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s.

Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.

Diagnosis/testing. The diagnosis of an NCL is increasingly based on assay of enzyme activity and molecular genetic testing. In unusual cases diagnosis relies on electron microscopy (EM) of biopsied tissues. The diagnostic testing strategy in a proband depends on the age of onset. Mutations in thirteen genes — PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, KCTD7 — are known to cause NCL.

Management. Treatment of manifestations: Treatment is currently symptomatic and palliative only. Seizures, malnutrition, gastroesophageal reflux, pneumonia, sialorrhea, depression and anxiety, spasticity, Parkinsonian symptoms, and dystonia can be effectively managed. Antiepileptic drugs (AEDs) should be selected with caution. Benzodiazepines may help control seizures, anxiety, and spasticity. Trihexyphenydate may improve dystonia and sialorrhea. Individuals with swallowing problems may benefit from placement of a gastric (G) tube. Antidepressants and antipsychotic agents are sometimes indicated for those with CLN3 disease.

Surveillance: Routine medical management of children and young adults with complex neurodisability will be relevant to all those affected by NCL, and may include surveillance for swallowing difficulties and recurrent aspiration; radiograph surveillance of hip joints and spine; screening ECG for those with CLN3 disease who are over age 16 years.

Agents/circumstances to avoid: Carbamazepine and phenytoin may increase seizure activity and myoclonus and result in clinical deterioration; lamotrigine may exacerbate seizures and myoclonus, especially in CLN2 disease.

Genetic counseling. The NCLs are inherited in an autosomal recessive manner with the exception of adult onset, which can be inherited in either an autosomal recessive or an autosomal dominant manner.

Autosomal recessive NCL. The parents of a child with an autosomal recessive form of NCL are obligate heterozygotes, and therefore carry one mutant allele. Heterozygotes have no symptoms. At conception, each sib has 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. Carrier testing for at-risk relatives is possible if the disease-causing mutations in the family are known.

Prenatal testing for pregnancies at increased risk is possible if the proband has documented deficient enzyme activity or if the disease-causing mutation(s) have been identified in the family.

Diagnosis

Schulz et al [2013] provides a diagnostic algorithm for the neuronal ceroid-lipofuscinoses (NCLs).

Clinical Diagnosis

Clinically, the NCLs are characterized by the following (Table 1):

  • Seizures
  • Progressive deterioration of cognition (dementia)
  • Motor function impairment (involuntary movements, myoclonus in younger children, ataxia, spasticity)
  • Vision loss

The first presenting symptom may vary among NCL phenotypes, which are typically distinguished on the basis of age of onset and clinical manifestations. Unusual mutations in many, if not all, NCL-associated genes may result in a milder or more severe disease phenotype.

Table 1. NCL Phenotypes and Their Known Associated Genes

PhenotypePhenotype by Gene and OnsetPresenting Findings 1
Proportion Gene SymbolAge of Onset
CongenitalMinor CTSDBefore or around birthSz, microcephaly
Infantile (INCL) MajorPPT16-24 mosCognitive/motor decline, ↓VA, Sz
RareKCTD7
Late-infantile (LINCL)ClassicMajorTPP12-4 yrsSz, motor/cognitive decline, ↓VA
Variant Major in Finland;
minor elsewhere
CLN54-7 yrsCognitive/motor decline, Sz, ↓VA
MinorCLN618 mos - 8 yrs Cognitive/motor decline, Sz, ↓VA
MinorMFSD8Cognitive/motor decline, Sz, ↓VA
MinorCLN83-7.5 yrsMotor decline, Sz, ↓VA
RareCTSD
MinorPPT1
Juvenile (JNCL) ClassicMajorCLN34-10 yrs↓VA, Sz, cognitive/motor decline, neuropsychiatric
VariantMinorPPT1
RareTPP1
RareCLN9 2
RareATP13A2
Northern epilepsy (NE)
(progressive epilepsy with
mental retardation [EPMR])
Major in Finland, rare elsewhereCLN85-10 yrsSz, cognitive decline, sometimes ↓VA
Adult (ANCL) (Kufs disease)RareCTSD, PPT1, CLN3, CLN5, CLN6, CTSF, GRN15-50 yrsCognitive/motor decline, Sz (type A), behavior abnormalities (type B)
Adult (ANCL) (Parry disease); autosomal dominantUnknownDNAJC5

1. Cognitive/motor decline, vision loss (↓VA), and seizures appear (Sz) in the order in which they are most likely to occur in each phenotype

2. Locus name; gene unknown

Testing

Histologic findings. Electron microscopy (EM) studies can be performed with 5-10 mL of heparinized whole blood (lymphocytes) or tissue biopsies (now usually of skin, but previously of conjunctiva or other tissues). EM studies (Table 2) remain essential in the non-classical NCL types, and show the presence of the following:

  • Granular osmiophilic deposits (GROD) in CLN1 disease and CLN10/CTSD forms
  • Predominantly curvilinear profiles (CVB) in CLN2 disease
  • Fingerprint profiles (FP) in CLN3 disease
  • Mixed-type inclusions (CVB, FP, and GROD) in CLN5, CLN6, MFSD8, CLN8, and other late-infantile and adult variant forms

Note: The appearance of the pathologic inclusions can depend on the tissue examined.

Enzyme activity. Three lysosomal enzymes (Table 2) have been identified as being deficient in the neuronal ceroid-lipofuscinoses in white blood cells, fibroblasts, and chorionic villi:

  • Palmitoyl-protein thioesterase 1 (PPT-1) encoded by PPT1. A fluorimetric assay for PPT-1 based on the fluorochrome 4-methylumbelliferone detects significantly reduced PPT-1 activity in leukocytes, fibroblasts, lymphoblasts, amniotic fluid cells, or chorionic villi in forms of NCL caused by PPT1 mutations [Voznyi et al 1999].
  • Tripeptidyl-peptidase 1 (TPP-1) encoded by TPP1. Individuals with TPP1 mutations usually have significantly reduced enzymatic activity in leukocytes, fibroblasts, amniotic fluid cells, or chorionic villi [Junaid et al 1999].
  • Cathepsin D (CTSD) encoded by CTSD. Individuals with CTSD mutations usually have significantly reduced enzymatic activity in leukocytes or fibroblasts.

A carrier of a mutation in PPT1, TPP1, or CTSD typically has 50% of normal enzymatic activity in PPT-1 or TPP-1 or CTSD, respectively [Das et al 1998, Zhong et al 1998, Sleat et al 1999, Zhong et al 2000a].

Table 2. Electron Microscopic Findings and Enzyme Activity by NCL Genotype

Locus NameGenePathologic Diagnosis on EM 1LymphocytesEnyzme Activity
CLN1PPT1GRODNot vacuolatedPPT-1 deficient
CLN2TPP1CVBNot vacuolatedTPP-1 deficient
CLN3CLN3FPVacuolatedNot applicable
CLN4DNAJC5GROD, mixed 2Not vacuolated
CLN5CLN5FPNot vacuolated
CLN6CLN6CVB, FP, RLNot vacuolated
CLN7MFSD8CVB, FP, RLNot vacuolated
CLN8CLN8CVB- or GROD-like structuresNot usually vacuolated
CLN9UnknownGROD, CVBNot vacuolatedUnknown; probably not applicable
CLN10CTSDGRODNot vacuolatedCTSD deficient
CLN11GRNFPNot vacuolatedNot applicable
CLN12ATP13A2GROD, MixedNot vacuolatedNot applicable
CLN13CTSFFP or noneNot vacuolatedCTSF-deficient
CLN14KCTD7GROD, FPNot vacuolatedNot applicable

CVB = curvilinear profiles

EM = electron microscopy

FP = fingerprint profiles

GROD = granular osmophilic deposits

PPT-1 = palmitoyl-protein thioesterase 1

RL = rectilinear complex

TPP-1 = tripeptidyl peptidase 1

1. In individuals with adult-onset disease, peripheral storage by EM may not be detected.

2. Mixed = CVB, FP, RL, GROD

Molecular Genetic Testing

Genes. PPT1, TPP1, CLN3, DNAJC5, CLN5, CLN6, CLN7/MFSD8, CLN8, CTSD, GRN, ATP13A2, CTSF, KCTD7 are the genes in which mutations are known to cause the neuronal ceroid-lipofuscinoses.

Evidence for locus heterogeneity

  • CLN9. The gene has not been identified in the families assigned this locus.

Table 3. Summary of Molecular Genetic Testing Used in NCL (see Table 1 for phenotypes associated with mutations in each gene)

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Gene and Test Method 3
PPT1Targeted mutation analysisp.Arg122Trp 4Finnish:98% 5
Non-Finnish: 10% 6 for the targeted variant
p.Arg151* 460% 6 for the targeted variant
Sequence analysisSequence variants 6>98% 7
Deletion/duplication analysis 8Exonic and whole-gene deletionsNot known
TPP1Targeted mutation analysisc.509-1G>C, p.Arg208* 460%-90% 9 for the targeted variant
Sequence analysisSequence variants 697% 9
CLN3Targeted mutation analysis c.461-280_677+382del 10 (1-kb deletion) 96% 11 for the targeted c.461-280_677+382del deletion
Sequence analysisSequence variants 6>98% 11
DNAJC5Sequence analysisSequence variants 6Not known, estimate >95%
CLN5Targeted mutation analysisp.Tyr392*94% (Finnish ancestry) 12
Sequence analysisSequence variants 6Est. 90%-95%
Deletion/duplication analysis 8Exonic and whole-gene deletionsNot known
CLN6Sequence analysisSequence variants 692% 13
Deletion/duplication analysis 8Exonic and whole-gene deletionsNot known
MFSD8Sequence analysisSequence variants 6Not known, est. >95%
CLN8Targeted mutation analysisp.Arg24Gly ~100% (Finnish ancestry) 14
Sequence analysisSequence variants 6Est. 90%-95%
Deletion/duplication analysis 8Exonic and whole-gene deletionsNot known
CTSDSequence analysisSequence variants 6Not known, est. >95%
GRNSequence analysisSequence variants 6Not known, est. >95%
ATP13A2Sequence analysisSequence variants 6Not known, est. >95%
CTSFSequence analysisSequence variants 6Not known, est. >95%
KCTD7Sequence analysisSequence variants 6Not known, est. >95%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene: % of individuals with at least one identifiable mutation

4. Mutation(s) included in targeted analysis may vary among laboratories.

5. PPT-1 enzyme-deficient individuals with INCL [Bellizzi et al 2000]

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. PPT-1 enzyme-deficient individuals [Das et al 1998, Hofmann et al 1999]

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. TPP-1 enzyme-deficient individuals with LINCL [Zhong et al 1998, Hartikainen et al 1999, Lauronen et al 1999, Sleat et al 1999, Zhong et al 2000b]

10. Common deletion of exons 7 and 8 (see Molecular Genetics)

11. Individuals with JNCL [Munroe et al 1997, Mao et al 2003, Mole et al 2004, Leman et al 2005]

12. Individuals of Finnish ancestry have variant LINCL and the CLN5 mutation (p.Tyr392*) [Savukoski et al 1998]

13. Families with vLINCL with linkage to CLN6 [Gao et al 2002, Sharp et al 2003, Teixeira et al 2003]

14. For individuals of Finnish ancestry [Ranta et al 2001, Ranta et al 2004]

Testing Strategy

The testing strategy to confirm/establish the diagnosis in a proband depends on the age of onset, and is summarized in Table 4.

  • If EM indicates typical NCL storage material, all NCL-related genes may eventually need to be tested by enzymatic activity or by sequencing.

Table 4. Diagnostic Algorithm for NCL Diseases

Clinical PresentationDiagnostic AlgorithmGene(s) for which Molecular Genetic Testing Should be Considered
Newborn with epilepsy and microcephalyEnzyme testing for CTSD (leukocytes or fibroblasts)
 • If CTSD deficient: CTSD
If CTSD enzyme activity is normal, consider enzyme assay for PPT-1 and TPP-1.
 • If PPT-1 deficient: PPT1
 • If TPP-1 deficient: TPP1
Young child (>6 months) with developmental standstill or regression and/or newly occurring severe epilepsy of unknown causeEnzyme testing for PPT-1 and TPP-1 (dry blood spots or leukocytes or fibroblasts)
 • If PPT-1 deficient:PPT1
 • If TPP-1 deficient: TPP1
If PPT-1 and TPP-1 enzyme activities are normal, electron microscopic examination (skin biopsy or lymphocytes)
 • If storage material is present: CLN5, CLN6, MFSD8, CLN8, KCTD7
School child with visual loss and/or dementia and epilepsySearch for lymphocyte vacuoles (light microscopy of blood smear).
 • If lymphocyte vacuoles are present: CLN3
If no lymphocyte vacuoles, enzyme testing for PPT-1, TPP-1 and CTSD
 • If PPT-1 deficient:PPT1
 • If TPP-1 deficient:TPP1
 • If CTSD deficient:CTSD
If PPT-1 and TPP-1 enzyme activities are normal, electron microscopic examination (skin biopsy or lymphocytes)
 • If storage material is present:CLN5, CLN6, MFSD8, CLN8, ATP13A2
Young adult with non-specific mental, motor, or behavioral abnormalitiesEnzyme testing for PPT-1, TPP-1, CTSD, and CTSF
 • If PPT-1 deficient:PPT1
 • If TPP-1 deficient:TPP1
 • If CTSD deficient:CTSD
 • If CTSF deficient:CTSF
If enzyme activities are normal, electron microscopic examination (skin biopsy or lymphocytes)
If storage material is present, genetic testing (eventually in special cases even without detection of storage material); consider possible mode of inheritance.
 • If autosomal dominant:DNAJC5
 • If autosomal recessive:CLN6, GRN, CTSF

Adapted from Schulz et al [2013]; reprinted with permission from Elsevier

Carrier testing for relatives at risk for the autosomal recessive forms of NCL requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Enzymatically or genetically undefined cases. Store DNA and fibroblast cell lines and consult an NCL research scientist who may be able to access new research tests, or store samples until diagnostic tests become available.

Note: Cell banking is the storage of cell lines (typically derived from a skin biopsy) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking cells particularly when all of the genes responsible have not yet been identified, not all disease-causing mutations have been elucidated, or testing is available on a research or linkage basis only. These cells can also be used to supply unlimited DNA or RNA samples.

Clinical Description

Natural History

All individuals with a neuronal ceroid-lipofuscinosis (NCL) have progressive decline, an evolving cognitive and motor disorder, and seizures. With the exception of adult neuronal ceroid-lipofuscinosis (ANCL) and Northern epilepsy (NE), NCL phenotypes are usually associated with progressive loss of vision.

A direct correlation between the gene that is mutated and phenotype does not always exist (see Table 1 and Genotype-Phenotype Correlations); for example, individuals with mutations in PPT1 can present with four different phenotypes (infantile, late-infantile, juvenile, and adult onset). Nonetheless, describing the NCLs by clinical phenotype is useful for medical management and prognosis [Das et al 1998, Wiśniewski et al 1998a, Wiśniewski et al 1999, van Diggelen et al 2001, Wiśniewski et al 2001].

CLN1 Disease, Classic Infantile (previously Classic Infantile NCL, INCL, Santavuori-Haltia)

CLN1 disease usually presents between age six and 24 months. Onset before age six months and after age two years also occurs [Das et al 1998, Wiśniewski et al 1998a, Wiśniewski et al 1999, van Diggelen et al 2001, Wiśniewski et al 2001].

Initial signs include: delayed development, myoclonic jerks, and/or seizures. In one series of 21 affected children, early signs were deceleration of head growth and specific electroencephalographic (EEG) changes (from age 13 months). Hand stereotypies resembling those seen in Rett syndrome are recognized. In a study of eight newly diagnosed children with INCL (ages 15-27 months), mild-to-moderate deterioration of intellectual ability was observed in all [Riikonen et al 2000]. The children had speech problems and lost interest in playing and in toys, but remained interested in their surroundings. They had moderate motor dysfunction.

Retinal blindness and seizures are evident by age two years. The ERG (electroretinogram) is unrecordable by age four years.

Psychomotor abilities deteriorate rapidly. Life expectancy varies from age two to nine years.

MRI findings are: variable cerebral atrophy; signal change in the thalami and basal ganglia; and thin, hyperintense, periventricular high-signal rims of white matter [Riikonen et al 2000]. The progressive diffuse brain atrophy on MRI seen in children with INCL during the first four years of life then stabilizes.

CLN2 Disease, Classic Late Infantile (previously Late-Infantile NCL, LINCL,

Jansky-Bielschowsky Disease)

The first symptoms of CLN2 disease typically appear between age two and four years, usually starting with epilepsy. Generalized tonic-clonic seizures, absences, and partial-onset seizures may be observed. Myoclonus becomes prominent after the onset of seizures. Sometimes slowing of developmental milestones is evident before the onset of seizures. Following the onset of seizures, previously acquired motor/language and cognitive skills are lost.

Visual impairment appears between age four and six years and rapidly progresses to blindness.

Affected children are usually bedridden by age six years; disabilities are severe and nursing care needs are considerable by mid-childhood. Life expectancy is between age six years and adolescence but can be longer [Wiśniewski et al 1998a, Wiśniewski et al 1999].

Early electroencephalogram (EEG) may show spikes in the occipital region in response to photic stimulation at 1-2 Hz. Electroretinogram (ERG) is usually abnormal at presentation and becomes undetectable soon thereafter. On occasion, the ERG may be normal at presentation [Weleber 1998].

Visual evoked potentials (VEPs) are enhanced for a long period and diminish in the final stage of the disease.

MRI shows progressive cerebellar and cerebral atrophy with normal basal ganglia and thalami.

Variants of late-infantile NCL. Many variant types are caused by mutations in distinct genes (Table 1). Some variant types are associated with but not exclusive to certain ethnic origins.

The clinical features of variant late-infantile NCL types may have typical characteristics, but in general overlap:

  • CLN5 disease, variant late infantile. The onset of disease is usually ages 4.5 to seven years in Finland. Life expectancy is between 13 and 35 years.
  • CLN6 disease. Visual loss and seizures may be the initial signs and symptoms. In children with onset after age four years, epilepsy, ataxia, and myoclonus may be the initial features.
  • MFSD8/CLN7 disease. Visual loss and seizures may be the initial signs and symptoms. In children with onset after age four years, epilepsy, ataxia, and myoclonus may be the initial features.
  • CLN8 disease. Onset may be earlier, between age two and six years [Sharp et al 2003].
  • Genetically undefined

CLN3 Disease (previously Classic Juvenile NCL, JNCL, Batten Disease, Spielmeyer-Vogt Disease)

Onset is usually between age four and eight years (mean age ~5 years).

Rapidly progressing vision loss is almost always the first clinical sign of the disease and may be the only sign for two to five years. Children become severely visually impaired within two to four years of the onset of vision loss. Ophthalmologic examination early in the course of JNCL may reveal macular changes only; gradually, typical signs of pan-retinal degeneration develop: pigmentary changes in the retinal periphery, vascular attenuation, and optic nerve pallor. ERG shows loss of photoreceptor function early on [Weleber 1998].

Epilepsy with generalized tonic-clonic seizures and/or focal-onset seizures typically appears between age nine and 18 years. The EEG shows nonspecific disorganization and spike-and-slow-wave complexes.

Little variation is observed in the visual symptoms and seizures, but variation can occur in the progression of motor and intellectual deterioration. Speech disturbances (festinating stuttering, often mislabeled as echolalia) and slow decline in cognition occur around the time of onset of seizures.

Behavioral problems, extrapyramidal signs, and sleep disturbance occur in the second decade. Backman et al [2005] found that some individuals with JNCL experience multiple psychiatric problems including disturbed thoughts, attention problems, somatic complaints, and aggressive behavior. Depression was uncommon.

There is recent evidence of cardiac involvement late in the disease: progressive cardiac involvement with repolarization disturbances, ventricular hypertrophy, and sinus node dysfunction [Ostergaard et al 2011].

Most individuals with CLN3 disease live until the late teens or early 20s; some may live into their 30s.

CT and MRI reveal cerebral, and to a lesser degree, cerebellar atrophy in the later stages (age >15 years).

Atypical JNCL. Individuals with atypical JNCL are often compound heterozygotes for CLN3 mutations (c.461-280_677+382del and another mutation). For example, p.Glu295Lys is associated with a particularly protracted disease in which a high level of functioning can be maintained for several decades. In other examples onset of epilepsy was delayed for a decade or more. The cause of these phenotypic differences is unknown. All variants with mutations in CLN3 have visual failure but vary in the severity of seizures and other neurologic complications.

JNCL variants are also caused by milder mutations in genes that usually cause a more severe NCL, in particular CLN1.

JNCL variant - CLN9. Two families in which the underlying gene is not known have been described [Schulz et al 2004].

Adult NCL (ANCL)

Initial signs and symptoms usually appear around age 30 years, with death occurring about ten years later. Symptoms may appear as early as age 11 years or much later in adulthood. Ophthalmologic studies are normal.

The two major clinical phenotypes are:

  • Type A, characterized by progressive myoclonic epilepsy with dementia, ataxia, and late-occurring pyramidal and extrapyramidal signs. Seizures are often uncontrollable. Individuals with this type have been found to have mutations in CLN6; it is now known as adult CLN6 disease.
  • Type B, characterized by behavior abnormalities and dementia, which may be associated with motor dysfunction, ataxia, extrapyramidal signs, and suprabulbar (brain stem) signs. Some families have been found to have mutations in CTSF.

In the presenile form with onset after age 50 years, dementia, cognitive decline, motor dysfunction, seizures, and suprabulbar signs are observed as well as mixed inclusions on EM (Table 2).

Autosomal dominant forms of adult-onset NCL have GROD observed on EM (Table 2) [Burneo et al 2003, Nijssen et al 2003], with some having mutations in DNAJC5. The genetically defined cases of recessive adult-onset NCL include several individuals with deficient PPT-1 enzyme activity [van Diggelen et al 2001, Ramadan et al 2007], deficient CTSD enzyme activity [Author, unpublished], or mutations in CLN5. Adult-onset disease, previously known as Kufs disease type A, results from mutations in CLN6 [Arsov et al 2011]; some cases of Kufs disease type B result from reduced CTSF activity [Smith et al 2013]. It is highly likely that a mild mutation in all known NCL-associated genes could delay disease onset until adulthood.

Northern Epilepsy (NE, Progressive Epilepsy with Mental Retardation, EPMR)

Northern epilepsy is a specific phenotype caused by a particular mutation in CLN8, and is characterized by epilepsy with tonic-clonic or complex-partial seizures, slow intellectual deterioration, and motor dysfunction.

Vision problems are rare.

The frequency of the epileptic manifestations decreases after puberty, but slow cognitive decline continues throughout life. Some individuals have lived beyond age 60 years.

Genotype-Phenotype Correlations

Mutations in the following NCL-related genes can be associated with both early and late age of onset – the latter probably the result of greater amounts of residual protein activity:

  • CLN10/CTSD. Congenital, late-infantile, or teenage-/adult-onset NCL
  • CLN1/PPT1. Infantile, late-infantile, juvenile, and adult-onset NCL
  • CLN2/TPP1. Late-infantile, juvenile, and possibly later-onset NCL
  • CLN5. Late-infantile variant, juvenile, and adult-onset NCL
  • CLN6. Late-infantile variant, and adult-onset NCL
  • CLN8. Late-infantile variant NCL and EPMR

Later ages of onset have not yet been described for CLN3 or CLN7/MFSD8.

Nomenclature

Neuronal ceroid-lipofuscinoses nomenclature is now gene based [Williams & Mole 2012].

Table 5. Former NCL Nomenclature

EponymDiseaseOMIM NumberClinical PhenotypeFormer Abbreviated Name
Haltia-SantavuoriCLN1256730Infantile classicINCL
Janský-BielschowskyCLN2204500Late-infantile classicLINCL
Spielmeyer-SjögrenCLN3204200JuvenileJNCL
Kufs type ACLN6204300Adult ANCL
Kufs type BCLN13AdultANCL
Finnish variant late infantileCLN5256731Late-infantile variantvLINCL
Lake-Cavanagh or Indian variant late infantileCLN6601780Early-juvenile variant and late-infantile variantvLINCL
Turkish variant late infantileCLN7610951Late-infantile variantvLINCL
Northern epilepsy/EPMRCLN8600143EPMR, late-infantile variantvLINCL
ParryCLN4162350Adult autosomal dominantANCL

Adapted from Williams & Mole [2012]

Batten disease was originally used to refer only to what is now known to be classic CLN3 disease. However, more recently it is being used to provide an accessible name for all types of NCL, regardless of genetic alteration.

Incidence and Prevalence

Neuronal ceroid-lipofuscinoses (NCLs) are the most common hereditary progressive neurodegenerative disease with a prevalence of approximately 1.5 to nine per million population [Mole et al 2011].

The incidence of NCL ranges in different countries from 1.3 to seven per 100,000 live births [Mole et al 2011].

Differential Diagnosis

In a UK epidemiologic study of progressive intellectual and neurologic deterioration over 12 years, 147 different diagnoses were recorded in 1114 of 2636 patients younger than age 16 years. The six most common groups of disorders were leukoencephalopathies (183 cases), neuronal ceroid-lipofuscinoses (141), mitochondrial disorders (122), mucopolysaccharidoses (102), gangliosidoses (100), and peroxisomal disorders (69) [Verity et al 2010].

CLN1 disease. Other progressive neurologic diseases with onset from birth to age two years need to be considered. These include: hexosaminidase A deficiency, progressive leukodystrophies Rett syndrome, peroxisomal biogenesis disorders, Neimann-Pick disease types A and B (see Acid Sphingomyelinase Deficiency), and Leigh syndrome (see also Mitochondrial Disorders Overview). While some of these disorders are associated with cortical blindness, retinal involvement is rarely seen.

CLN2 disease. Other progressive neurologic diseases with onset from ages two to four years need to be considered. These include: epileptic encephalopathies, other lysosomal storage disorders, mitochondrial disease, and leukodystrophies.

CLN3 disease. In the initial stage when individuals present with visual loss, retinitis pigmentosa (RP) or cone-rod dystrophy may be considered. The ophthalmologic involvement of JNCL differs from classic RP in that the vision loss in CLN3 disease is typically central at first (rather than peripheral) and rapidly progressive, with total blindness occurring in one to two years [Weleber 1998]. In contrast, RP is indolent and progresses slowly over decades. Other disorders in which a cone-rod retinal dystrophy occurs are: Bardet-Biedl syndrome, Joubert syndrome, juvenile nephronophthisis, and Alstrom syndrome, all of which can be distinguished from CLN3 disease by their clinical features.

Northern epilepsy (NE) needs to be distinguished from other neurologic conditions with seizures [Zupanc & Legros 2004]. Myoclonus is not a feature of NE, and thus a large number of disorders with myoclonic seizures and intellectual disability can be excluded. The clinical course of NE differs from Landau-Kleffner syndrome, Rasmussen syndrome, and epilepsy with electric status epilepticus during slow sleep. Tuberous sclerosis complex and the Sturge-Weber syndrome can be distinguished from NE on the basis of clinical and neuroradiologic features. Lack of pyramidal or extrapyramidal signs and lack of cerebellar ataxia distinguish NE from degenerative disorders such as: juvenile Huntington disease, PKAN (previously called Hallervorden-Spatz syndrome), juvenile GM2 gangliosidosis (see Hexosaminidase A deficiency), Niemann-Pick disease type C, giant axonal neuropathy, or neuronal intranuclear inclusion disease [OMIM 603472].

Adult Kuf’s disease. The differential diagnosis includes progressive myoclonic epilepsies (see Lafora Progressive Myoclonus Epilepsy), Unverricht-Lundborg disease, mitochondrial disease including MERRF (see also Mitochondrial Disease Overview); early-onset dementias, Creutzfeldt-Jakob Disease (CJD) (see Genetic Prion Diseases) and dentatorubral-pallidoluysian atrophy (DRPLA).

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with one of the neuronal ceroid-lipofuscinoses, the following evaluations are recommended:

  • Neurologic examination
  • Ophthalmologic examination
  • Developmental/cognitive and educational assessment
  • Medical genetics consultation

Treatment of Manifestations

Symptomatic treatment can be successful in mitigating the manifestations of NCL. Seizures, sleep-related problems, malnutrition, gastroesophageal reflux, pneumonia, sialorrhea, hyperactivity and behavior problems, psychosis, anxiety, spasticity, Parkinsonian symptoms, and dystonia can be palliated.

Seizures. Antiepileptic drugs (AEDs) should be selected with caution. The stage of the disease, age of the affected individual, and quality of life are important to consider in evaluating the effectiveness of AEDs.

Lamotrigine (LTG) had a favorable effect on 23/28 individuals with JNCL, 13/19 being continued on monotherapy with 100% control, compared to 70% control for those receiving valproic acid (VPA), 60% control for VPA-clonazepam (CZP), and 60% control for LTG-CZP [Aberg et al 1999, Aberg et al 2000].

Other newer AEDs including levetiracetam and topiramate may also be beneficial [Author, personal experience].

Other. Benzodiazepines may be of benefit for seizures, anxiety, spasticity, and sleep disorders.

Trihexyphenydil improves dystonia and sialorrhea.

Individuals with swallowing problems may benefit from placement of a gastric (G) tube.

Antidepressants and antipsychotic agents are sometimes indicated for those with CLN3 disease.

Surveillance

Routine medical management of children and young adults with complex neurodisability will be relevant to all those affected by NCL. This may include clinical surveillance for the following:

  • Swallowing difficulties and recurrent aspiration
  • X-ray surveillance of hip joints and spine
  • Screening ECG for those individuals with CLN3 disease who are older than age 16 years

Agents/Circumstances to Avoid

Carbamazepine (CZP) and phenytoin may increase seizure activity and myoclonus in NCL and result in clinical deterioration.

Lamotrigine may exacerbate seizures and myoclonus especially in CLN2 disease.

In a series of 60 individuals with JNCL, valproic acid (VPA) was withdrawn in 20% and clonazepam (CZP) in 16% because of side effects [Aberg et al 2000].

  • Fifty percent of individuals receiving VPA had sleep disturbances or excessive sedation.
  • CZP stimulates salivation and respiratory secretions, increasing the risk for pneumonia in bedridden individuals, many of whom have gastroesophageal reflux. CZP is a sedative and can cause behavior disturbances.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Crystal et al [2004] initiated gene therapy for children with LINCL caused by mutations in CLN2. They administered a replication-deficient adeno-associated virus (AAV) vector expressing human CLN2 cDNA directly into the brains of children with either severe or moderate LINCL in an attempt to produce sufficient amounts of TPP-1, to prevent further loss of neurons and hence limit disease progression. The research is ongoing.

Stem cell therapy for phenotypes caused by mutations in CLN1 and CLN2 is in progress [Author, personal communication].

The drug EGIS-8332, which targets AMPA receptors, improved performance in a CLN3 disease mouse model. Trials in humans have not yet started. Talampanel (LY300164) is a drug which targets the same receptors and is being assessed in a clinical trial to treat epilepsy and Parkinson disease in humans. Plans to test this drug in a mouse model for CLN3 disease are underway at the University of Rochester Medical Center (Rochester, New York, USA).

The University of Rochester Medical Center is also conducting a clinical trial using the immunosuppressant mycophenolate (mycophenolate mofetil, Cellcept, Myfortic, mycophenolate sodium or mycophenolic acid) in individuals with juvenile CLN3.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The NCLs are inherited in an autosomal recessive manner with the exception of adult NCL, which can be inherited in either an autosomal recessive or an autosomal dominant manner.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele). Obtaining parental samples to confirm carrier status is recommended once mutations have been identified in the proband.
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of a proband has 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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes are asymptomatic.

Offspring of a proband

  • Probands with INCL, LINCL, and classic JNCL do not reproduce.
  • Very rarely, individuals with atypical JNCL reproduce [Wiśniewski et al 1998b]. The offspring of an individual with NCL are obligate heterozygotes (carriers) for a mutant allele causing NCL.

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

Carrier Detection

Carrier testing by DNA analysis is possible once the mutations in the underlying gene have been identified in the family.

Risk to Family Members — Autosomal Dominant Inheritance (adult NCL only)

Parents of a proband

  • Most individuals diagnosed with autosomal dominant adult NCL have an affected parent.
  • A proband with autosomal dominant adult NCL may have the disorder as the result of a de novo mutation. The proportion of cases caused by de novo mutations is unknown.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing of the identified mutation. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although most individuals diagnosed with autosomal dominant adult NCL have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a parent.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant adult NCL has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is possible in pregnancies at increased risk if biochemical studies in the proband have revealed deficient activity of the enzyme CTSD, PPT-1, or the enzyme TPP-1, or if the disease-causing mutation(s) have been identified in the proband and parents. In these instances, testing is performed on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or amniocentesis usually performed at about 15 to 18 weeks' gestation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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.

  • Batten Disease Family Association (BFDA)
    c/o Heather House
    Heather Drive
    Tadley Hampshire RG26 4QR
    United Kingdom
    Phone: 01603 760111; 01233 639526
    Email: info@bdfa-uk.org.uk; support@bdfa-uk.org.uk
  • Batten Disease Support and Research Association (BDSRA)
    166 Humphries Drive
    Reynoldsburg OH 43068
    Phone: 800-448-4570 (toll-free); 740-927-4298
    Email: bdsra1@bdsra.org
  • NCL Resource - A Gateway for Batten Disease
    MRC Laboratory for Molecular Cell Biology, University College London
    Gower Street
    London WC1E 6BT
    United Kingdom
    Phone: +00 44 207 679 7257
    Email: ncl-www@ucl.ac.uk
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • Children's Brain Disease Foundation
    Parnassus Heights Medical Building
    350 Parnassus Avenue
    Suite 900
    San Francisco CA 94117
    Phone: 415-665-3003
    Fax: 415-665-3003
    Email: jrider6022@aol.com
  • National Tay-Sachs and Allied Diseases Association, Inc. (NTSAD)
    2001 Beacon Street
    Suite 204
    Boston MA 02135
    Phone: 800-906-8723 (toll-free)
    Fax: 617-277-0134
    Email: info@ntsad.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Neuronal Ceroid-Lipofuscinoses: Genes and Databases

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
CLN1PPT11p34​.2Palmitoyl-protein thioesterase 1Finnish Disease Database (PPT1)
Retina International Mutations of the Palmitoyl-Protein Thioesterase Gene (PPT CLN1) Gene (PPT1)
Neuronal Ceroid Lipofuscinoses; NCL Mutations (PPT1)
PPT1 database
PPT1
CLN2TPP111p15​.4Tripeptidyl-peptidase 1Neuronal Ceroid Lipofuscinoses; NCL Mutations (TPP1)
TPP1 database
TPP1
CLN3CLN316p11​.2BatteninFinnish Disease Database (CLN3)
Retina International Mutations of the CLN3 Gene
Neuronal Ceroid Lipofuscinoses; NCL Mutations (CLN3)
CLN3 database
CLN3
CLN4DNAJC520q13​.33DnaJ homolog subfamily C member 5DNAJC5 @ LOVD
Neuronal Ceroid Lipofuscinoses; NCL Mutations (DNAJC5)
DNAJC5
CLN5CLN513q22​.3Ceroid-lipofuscinosis neuronal protein 5Finnish Disease Database (CLN5)
Neuronal Ceroid Lipofuscinoses; NCL Mutations (CLN5)
CLN5 database
CLN5
CLN6CLN615q23Ceroid-lipofuscinosis neuronal protein 6Neuronal Ceroid Lipofuscinoses; NCL Mutations (CLN6)
CLN6 database
CLN6
CLN7MFSD84q28​.2Major facilitator superfamily domain-containing protein 8Neuronal Ceroid Lipofuscinoses; NCL Mutations (MFSD8)
MFSD8 database
MFSD8
CLN8CLN88p23​.3Protein CLN8Finnish Disease Database (CLN8)
Neuronal Ceroid Lipofuscinoses; NCL Mutations (CLN8)
CLN8 database
CLN8
CLN9UnknownUnknownUnknown
CLN10CTSD11p15​.5Cathepsin DNeuronal Ceroid Lipofuscinoses; NCL Mutations (CTSD)
CTSD database
CTSD
CLN11GRN17q21​.31GranulinsAlzheimer Disease & Frontotemporal Dementia Mutation Database (GRN)
Neuronal Ceroid Lipofuscinoses; NCL Mutations (GRN)
GRN database
GRN
CLN12ATP13A21p36​.13Probable cation-transporting ATPase 13A2ATP13A2 @ LOVDATP13A2
CLN13CTSF11q13​.2Cathepsin FCTSF @ LOVD
Neuronal Ceroid Lipofuscinoses; NCL Mutations (CTSF)
CTSF
CLN14KCTD77q11​.21BTB/POZ domain-containing protein KCTD7Neuronal Ceroid Lipofuscinoses; NCL Mutations (KCTD7)
KCTD7 database
KCTD7

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Neuronal Ceroid-Lipofuscinoses (View All in OMIM)

116840CATHEPSIN D; CTSD
138945GRANULIN PRECURSOR; GRN
162350CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT; CLN4B
204200CEROID LIPOFUSCINOSIS, NEURONAL, 3; CLN3
204300CEROID LIPOFUSCINOSIS, NEURONAL, 4A, AUTOSOMAL RECESSIVE; CLN4A
204500CEROID LIPOFUSCINOSIS, NEURONAL, 2; CLN2
256730CEROID LIPOFUSCINOSIS, NEURONAL, 1; CLN1
256731CEROID LIPOFUSCINOSIS, NEURONAL, 5; CLN5
600143CEROID LIPOFUSCINOSIS, NEURONAL, 8; CLN8
600722PALMITOYL-PROTEIN THIOESTERASE 1; PPT1
601780CEROID LIPOFUSCINOSIS, NEURONAL, 6; CLN6
603539CATHEPSIN F; CTSF
606725CLN6 GENE; CLN6
607042CLN3 GENE; CLN3
607837CLN8 GENE; CLN8
607998TRIPEPTIDYL PEPTIDASE I; TPP1
608102CLN5 GENE; CLN5
609055CEROID LIPOFUSCINOSIS, NEURONAL, 9; CLN9
610127CEROID LIPOFUSCINOSIS, NEURONAL, 10; CLN10
610513ATPase, TYPE 13A2; ATP13A2
610951CEROID LIPOFUSCINOSIS, NEURONAL, 7; CLN7
611124MAJOR FACILITATOR SUPERFAMILY DOMAIN-CONTAINING PROTEIN 8; MFSD8
611203DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 5; DNAJC5
611725POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 7; KCTD7
611726EPILEPSY, PROGRESSIVE MYOCLONIC 3, WITH OR WITHOUT INTRACELLULAR INCLUSIONS; EPM3
614706CEROID LIPOFUSCINOSIS, NEURONAL, 11; CLN11

Molecular Genetic Pathogenesis

Both human and animal forms of neuronal ceroid-lipofuscinoses can be divided into two major groups, based on the nature of the material accumulated in lysosomes:

  • Those characterized by the prominent storage of saposins (SAPs) A and D; and
  • Those showing the predominance of subunit c of mitochondrial ATP synthase accumulation.

In addition to proteins, storage material in NCLs contains other components including lipids, metals, dolichyl pyrophosphoryl oligosaccharides, and lipid thioesters.

The relation between genetic defects associated with the major NCL forms, the accumulation of storage material, and tissue dysfunction and/or damage is still unknown. Furthermore, all individuals with NCLs manifest lysosomal storage in many tissues and organs, but severe degeneration and cell loss involve mostly neuronal cells. Thus, it appears that NCL proteins may be most critical for the metabolism of neurons. It is uncertain whether this phenomenon results from the specific metabolic requirements of a neuron as a postmitotic cell, or from the properties of NCL proteins per se.

The spectrum of mutations present in NCL is listed in the NCL Mutation Database www.ucl.ac.uk/ncl (see also Table A).

PPT1

Normal allelic variants. The gene comprises nine exons spanning 25 kb.

Pathologic allelic variants. More than 60 mutations of PPT1 are known. The common mutations are p.Arg122Trp and p.Arg151* [Das et al 1998]; the others are uncommon or private mutations.

Table 6. PPT1 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.364A>Tp.Arg122TrpNM_000310​.2
NP_000301​.1
c.451C>Tp.Arg151*

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. PPT-1 is a globular enzyme consisting of six parallel β strands alternating with α helices organized in a structure known as the α/β hydrolast fold typical of lipases. A large insertion between β6 and β7 (amino acid residues 140-223) forms a second domain that forms most of the fatty acid-binding site. Catalytic active site residues are: Ser115, Asp233, and His289. PPT-1 is a housekeeping enzyme present in the lysosomes of many tissues. It removes long-chain fatty acids, usually palmitate, from cystine residues.

Based on the results of crystallographic and molecular modeling studies of recombinant bovine PPT-1 enzyme, a mechanism has been hypothesized to explain the milder INCL phenotype in individuals with PPT1 mutations who retain low-level thioesterase activity [Bellizzi et al 2000].

Abnormal gene product. Mutations affect PPT-1 in different ways. For some the protein is truncated, lacking its catalytic site; for others critical residues, such as within the catalytic site, are absent or altered.

TPP1

Normal allelic variants. TPP1 comprises 13 exons.

Pathologic allelic variants. More than 90 mutations of TPP1 are known. The common mutations are p.Arg208* and c.509-1G>C [Zhong et al 1998, Sleat et al 1999]; the others are uncommon or private mutations.

Table 7. TPP1 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.622C>Tp.Arg208*NM_000391​.3
NP_000382​.3
c.509-1G>C
(IVS5-1G>C)
--

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. TPP-1 comprises 365 amino acids. It is a lysosomal serine-carboxyl peptidase that sequentially removes N-terminal tripeptides from small peptides, including several peptide hormones.

Abnormal gene product. Mutations affect TPP-1 in different ways. For some the protein is truncated, lacking its catalytic site; for others critical residues, such as within the catalytic site, are absent or altered.

CLN3

Normal allelic variants. The gene comprises 15 exons.

Pathologic allelic variants. More than 50 mutations are presently known. The common mutation is a c.461-280_677+382del [Munroe et al 1997]; the others are uncommon or private mutations. The c.461-280_677+382del mutation deletes 217 bp of coding sequence, but the breakpoints are in intronic regions and the total deletion is approximately 1 kb and includes exons 7 and 8. The genomic DNA designation is NG_008654.1:g.10373_11338del.

Table 8. CLN3 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.461-280_677+382del (c.461_677del)p.Gly154Alafs*29NM_001042432​.1
NP_001035897​.1
c.88G>Ap.Glu295Lys

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. The protein comprises 438 amino acids; its function is unknown. CLN3 is most likely to be present in the lysosomal/endosomal membrane, and may also be in the Golgi complex and on the plasma membrane. In addition, CLN3 undergoes post-translational modification.

Abnormal gene product. Although the function of CLN3 remains elusive, it is apparent that genetic alterations in CLN3 may have a direct effect on lysosomal function. The most common mutation, the 1-kb deletion, does not completely abolish CLN3 function [Kitzmüller et al 2008].

DNAJC5

Normal allelic variants. The transcript has five exons [NM_025219.2].

Pathologic allelic variants. Two mutations have been described [Nosková et al 2011].

Normal gene product. The protein, DnaJ homolog subfamily C member 5, functions in many cellular processes by regulating the ATPase activity of 70-kd heat shock proteins [provided by RefSeq].

Abnormal gene product. Two mutations that cause disease when present on a single allele of DNAJC5 have been identified; the mechanism is unknown.

CLN5

Normal allelic variants. The gene comprises four exons.

Pathologic allelic variants. More than 30 mutations are known. The first affected individuals were in Finland; many cases have now been reported elsewhere. The mutation p.Tyr392* is observed in 94% of individuals of Finnish descent who have CLN5; the mutation p.Trp75* also segregates in affected individuals of Finnish descent. Other mutations are less common.

Table 9. CLN5 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.225G>Ap.Trp75*NM_006493​.1
NP_006484​.1
c.1175_1176delATp.Tyr392*

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The normal protein comprises 407 amino acids.

Abnormal gene product. CLN5 is a lysosomal transmembrane or soluble protein of unknown function.

CLN6

Normal allelic variants. The gene comprises seven exons.

Pathologic allelic variants. More than 60 mutations are known, including missense and nonsense mutations, small deletions or insertions, and splice site mutations. Affected individuals have been identified in many countries. The mutation p.Glu72* is common in persons from Costa Rica. The 1-bp insertion c.316dupC is associated with families from Pakistan; p.Ile154del may be common in Portugal. See Table 10.

Table 10. CLN6 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.214G>Tp.Glu72*NM_017882​.1
NP_060352​.1
c.316dupC
(c.316insC)
p.Arg106Profs*6
c.460_462delATCp.Ile154del

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. This transmembrane protein of unknown function resides in the endoplasmic reticulum (ER) [Mole et al 2004].

Abnormal gene product. Heine et al [2004] discuss the defective endoplasmic reticulum resulting from CLN6 mutations.

MFSD8

Normal allelic variants. The gene comprises 13 exons.

Pathologic allelic variants. More than 30 mutations are known. Mutations in MFSD8 were originally identified in persons of Turkish origin; cases from many countries have since been described. The most common mutation is p.Thr294Lys, which is associated with Roma Gypsies originating from the Czech Republic. Another common mutation is c.754+2T>A. See Table 11.

Table 11. MFSD8 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change Protein Amino Acid Change
c.881C>A 1p.Thr294Lys
c.754+2T>A 2(predicted altered splicing)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Kousi et al [2009]

2. Siintola et al [2007]

Normal gene product. MFSD8 is a member of the major facilitator superdomain family of transporter proteins.

Abnormal gene product. Unknown

CLN8

Normal allelic variants. The gene comprises three exons.

Pathologic allelic variants. More than 20 mutations are known. Many mutations have been reported in persons from several countries, including Turkey and Italy.

One group of individuals of Finnish origin, who are homozygous for the missense mutation p.Arg24Gly, have the allele-specific disease Northern epilepsy/EPMR disease [Ranta et al 2001]. Other mutations in CLN8 give rise to the vLINCL phenotype.

Table 12. CLN8 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.70C>Gp.Arg24GlyNM_018941​.3
NP_061764​.2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. This protein of 286 amino acids is localized to the ER and ER Golgi intermediate compartment.

Abnormal gene product. Unknown

CTSD (previously CLN10)

Normal allelic variants. The transcript NM_001909.4 comprises nine exons.

Pathologic allelic variants. Seven mutations are known. None is common (see Table A, Locus Specific).

Normal gene product. NP_001900.1 has 412 amino acid residues that encode cathepsin D light chain, a lysosomal aspartate protease.

Abnormal gene product. Unknown

GRN

Normal allelic variants. Transcript NM_002087.2 has 13 exons.

Pathologic allelic variants. Two NCL-causing mutations have been described [Smith et al 2012] (see Table A, Locus Specific).

Normal gene product. Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88-kd precursor protein, progranulin, is also called proepithelin [extracted from RefSeq]. Transcript NM_002087.2 encodes a mature peptide of 576 amino acids, NP_002078.1.

Abnormal gene product. A mutation on one disease allele only causes late-onset frontotemporal lobe degeneration with TDP-43 inclusions. Mutations on both disease alleles cause childhood-onset NCL. The mechanism is unknown.

ATP13A2

Normal allelic variants. The longest transcript variant NM_022089.2 has 29 exons and encodes the longest protein isoform. Other transcript variants have been found.

Pathologic allelic variants. One mutation that results in NCL has been described [Bras et al 2012].

Normal gene product. The protein product ATP13A2 is a P-type ATPase. The longest isoform NP_071372.1 has 1180 amino acids.

Abnormal gene product. Unknown

CTSF

Normal allelic variants. The transcript NM_003793.3 comprises 13 exons.

Pathologic allelic variants. Five mutations have been described [Smith et al 2013].

Normal gene product. The protein product, cathepsin F, has 484 amino acid residues. Cathepsins are papain family cysteine proteinases that represent a major component of the lysosomal proteolytic system [extracted from RefSeq].

Abnormal gene product. Unknown, but enzyme activity is presumably impaired.

KCTD7

Normal allelic variants. NM_153033.4 is the longest transcript variant and comprises four exons.

Pathologic allelic variants. One NCL-causing mutation has been described [Staropoli et al 2012].

Normal gene product. The gene product, BTB/POZ domain-containing protein KCTD7, is a potassium channel tetramerization domain-containing protein 7.

Abnormal gene product. Unknown, but different mutations cause different diseases.

References

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Chapter Notes

Author Notes

The original author, Dr. Wiśniewski, was a nationally and internationally known pediatric neurologist and neuropathologist/neurobiologist. She was the author or co-author of over 300 publications and numerous books and book chapters in the field of progressive neurogenetic diseases and intellectual and developmental disabilities.

Current author, Sara Mole PhD, is a research scientist with over 20 years’ experience in the neuronal ceroid lipofuscinoses. She curates the NCL Mutation Database, part of the NCL Resource web site, and is an author of many scientific articles, reviews and book chapters, including editor of a book on Batten disease.

Current author, Ruth Williams MD, is a pediatric neurologist specializing in epilepsy, with many years of special interest in the NCLs.

Author History

Sara E Mole, PhD (2010-present)
Ruth E Williams, MD (2010-present)
Krystyna E Wiśniewski, MD, PhD; New York State Institute for Basic Research in Developmental Disabilities (2001-2010)

Revision History

  • 1 August 2013 (me) Comprehensive update posted live
  • 2 March 2010 (me) Comprehensive update posted live
  • 17 May 2006 (me) Comprehensive update posted to live Web site
  • 15 August 2005 (bp) Revision: sequence analysis for CLN5 and CLN8 clinically available
  • 19 November 2004 (bp) Revision: CLN5 and CLN8 sequence analysis
  • 27 January 2004 (me) Comprehensive update posted to live Web site
  • 12 June 2003 (kw) Revision: testing
  • 10 October 2001 (me) Review posted to live Web site
  • 20 February 2001 (kw) Original submission
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