Clinical Diagnosis

Clinically, the neuronal ceroid-lipofuscinoses (NCLs) are characterized by the following (Table 1):

• Seizures
• Progressive deterioration of cognition (dementia)
• Motor function impairment (involuntary movement, ataxia, spasticity)
• Vision loss
  • The NCL phenotypes most often associated with progressive vision loss are:
    • Infantile neuronal ceroid-lipofuscinosis (INCL)
    • Late-infantile neuronal ceroid-lipofuscinosis (LINCL) - all types
    • Juvenile neuronal ceroid-lipofuscinosis (JNCL)
  • The NCL phenotypes most commonly not associated with vision loss are:
    • Adult neuronal ceroid-lipofuscinosis (ANCL) (Kufs disease)
    • Northern epilepsy (NE) or progressive epilepsy with mental retardation (EPMR)
    • Very rarely, variant late-infantile NCL caused by mutations in CLN8.

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-causing genes may result in a milder disease phenotype than that typically associated with complete loss of function.

Testing

Histologic findings. 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 osmophilic deposits (GROD) in CLN1/INCL and CLN10/CTSD forms
• Predominantly curvilinear profiles (CV) in CLN2/cLINCL
• Fingerprint profiles (FP) in JNCL
• Mixed-type inclusions (CV, FP, and GROD) in CLN5, CLN6, MFSD8, CLN8 and other late-infantile variant forms
• Mixed-type inclusions (CV, FP, and GROD) in ANCL 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 (PPT1) encoded by the gene PPT1. A fluorimetric assay for PPT1 based on the fluorochrome 4-methylumbelliferone detects no PPT1 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 the gene TPP1. Individuals with TPP1 mutations usually have no enzymatic activity in leukocytes, fibroblasts, amniotic fluid cells, or chorionic villi [Junaid et al 1999].
• Cathepsin D (CTSD) encoded by the gene CTSD. Individuals with CTSD mutations usually have no enzymatic activity in leukocytes or fibroblasts.
• A carrier of a mutation in PPT1, TPP1, or CTSD typically has 50% of normal enzymatic activity in PPT1 or TPP-1 or CTSD, respectively [Das et al 1998, Zhong et al 1998, Sleat et al 1999, Zhong et al 2000a].

Molecular Genetic Testing

Genes. The genes PPT1, TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, and CTSD are known to be associated with the neuronal ceroid-lipofuscinoses.

Other loci

• CLN4. The gene has not been identified.
• CLN9. The gene has not been identified.

Clinical testing

Table 3. Summary Molecular Genetic Testing Used in NCL (See Table 1 for Phenotypes Associated with Mutations in each Gene)

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
PPT1	Targeted mutation analysis	p.Arg122Trp 2	Finnish:98% 3 Non-Finnish: 10% 4 for the targeted variant	Clinical
		p.Arg151X 2	60% 4 for the targeted variant
	Sequence analysis	Sequence variants	>98% 4
TPP1	Targeted mutation analysis	c.509-1G>C, p.Arg208X 2	60%-90% 5 for the targeted variant	Clinical
	Sequence analysis	Sequence variants	97% 5
CLN3	Targeted mutation analysis	c.461-280_677+382del 6 (1-kb deletion)	96% 7 for the targeted c.461-280_677+382del deletion	Clinical
	Sequence analysis	Sequence variants	>98% 7
CLN5	Targeted mutation analysis	p.Tyr392X	94% (Finnish ancestry) 8	Clinical
	Sequence analysis	Sequence variants	Estimate 90%-95%
	Deletion/duplication analysis 9	Exonic and whole-gene deletions	Not known
CLN6	Sequence analysis	Sequence variants	92% 10	Clinical
MFSD8	Sequence analysis	Sequence variants	Not known, estimate >95%	Clinical
CLN8	Targeted mutation analysis	p.Arg24Gly	~100% (Finnish ancestry) 11	Clinical
	Sequence analysis	Sequence variants	Estimate 90%-95%
CTSD	Sequence analysis	Sequence variants	Not known, estimate >95%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Mutation(s) detected by targeted analysis may vary among laboratories.

3. PPT1 enzyme-deficient individuals with INCL [Bellizzi et al 2000]

4. PPT1 enzyme-deficient individuals [Das et al 1998, Hofmann et al 1999]

5. 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]

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

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

8. Individuals of Finnish ancestry have variant LINCL and the CLN5 mutation (p.Tyr392X) [Savukoski et al 1998]

9. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used.

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

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

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

The testing strategy to establish the diagnosis in a proband depends on the age of onset. See Figure 1:

Figure

Figure 1. Diagnostic algorithm for NCL. When attempting to diagnose NCL, the age of onset or ethnicity can help direct but not exclude testing.

If onset is around birth:

• Assay CTSD enzyme activity
• If CTSD enzyme activity is deficient, perform molecular genetic testing of CTSD to identify the family-specific mutations *
• If CTSD enzyme activity is normal, assay PPT1 and TPPI enzyme activity
• If PPT1 or TPP-1 enzyme activity is deficient, perform molecular genetic testing of PPT1 or TPP1 to identify the family-specific mutations *
• If CTSD, PPT1, and TPP-1 enzyme activity is normal and a skin biopsy shows suggestive storage material by EM, consider molecular genetic testing of CLN3, then other known NCL genes

* Note: Family-specific mutations are identified for carrier detection among at-risk family members and for prenatal diagnosis

If onset is between six months and two years:

• Assay PPT1 enzyme activity
• If PPT1 enzyme activity is deficient, perform molecular genetic testing of PPT1 to identify the family-specific mutations
• If PPT1 enzyme activity is normal, assay CTSD and TPP-1 enzyme activity
• If CTSD enzyme activity is deficient, perform molecular genetic testing of CTSD to identify the family-specific mutations
• If TPP-1 enzyme activity is deficient, perform molecular genetic testing of TPP1 to identify the family-specific mutations
• If PPT1, TPP-1, and CTSD enzyme activity is normal and a skin biopsy shows suggestive storage material by EM, consider molecular genetic testing of CLN3, then other known NCL genes

If onset is between ages two and five years and initial symptoms include seizures and developmental regression:

• Assay TPP-1 enzyme activity
• If TPP-1 enzyme activity is deficient, perform molecular genetic testing of TPP1 to identify the family-specific mutations
• If TPP-1 enzyme activity is normal, assay PPT1 and CTSD enzyme activity
• If PPT1 enzyme activity is deficient, perform molecular genetic testing of PPT1 to identify the family-specific mutations
• If CTSD enzyme activity is deficient, perform molecular genetic testing of CTSD to identify the family-specific mutations
• If TPP-1/PPT1/CTSD enzyme activity is normal and a skin biopsy shows suggestive storage material by EM, consider molecular genetic testing of CLN5, CLN6, MFSD8, and CLN8.

If onset is between ages five and 12 years, and initial symptoms include visual failure:

• Evaluate blood film for vacuolated lymphocytes
• If vacuolated lymphocytes are present, perform deletion/duplication analysis of CLN3
• If the common CLN3 deletion (c.461-280_677+382del) is not present, look for other mutations in CLN3.
• If no mutations in CLN3 are found, assay the enzyme activity of PPT1, TPP-1, and CTSD
• If PPT1 enzyme activity is deficient, perform molecular genetic testing of PPT1 to identify the family-specific mutations
• If TPP-1 enzyme activity is deficient, perform molecular genetic testing of TPP1 to identify the family-specific mutations
• If CTSD enzyme activity is deficient, perform molecular genetic testing of CTSD to identify the family-specific mutations
• If a skin biopsy shows suggestive storage material by EM, consider molecular genetic testing of CLN5, CLN6, MFSD8, CLN8, and any other known NCL-causing genes

If onset is after age 12 years (adulthood):

• Perform skin biopsy for EM
• If characteristic inclusions are present, assay PPT1, TPP-1 and CTSD enzyme activity
• If characteristic FP, RL, or CV inclusions are present, and CTSD/PPT1/TPP-1 enzyme activity is normal, pursue molecular genetic testing of all other genes associated with NCL.

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.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in the CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN5, CLN6, CLN7/MFSD8, or CLN8 genes.

It is a possible that other phenotypes are associated with non-1 kb deletion mutations of CLN3 [Kitzmüller et al 2008].

Natural History

All individuals with a neuronal ceroid-lipofuscinosis (NCL) have progressive decline, and 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 (INCL, LINCL, JNCL, and ANCL). Nonetheless, describing the NCLs by phenotype is clinically useful for diagnosis and prognosis [Das et al 1998, Wisniewski et al 1998a, Wisniewski et al 1999, van Diggelen et al 2001, Wisniewski et al 2001].

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.
• CLN8. Late-infantile variant NCL and EPMR.

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

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.

The incidence of NCL ranges in different countries from 1.3 to seven per 100,000 live births.

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
• Genetic evaluation

Treatment of Manifestations

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

Doxepin improves sleep, mood, and gastric emptying.

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

Agents/Circumstances to Avoid

Carbamazepine (CZP) and phenytoin may increase seizure activity in NCL and may be associated with clinical deterioration.

Lamotrigine may exacerbate seizures and myoclonus especially in LINCL/CLN2.

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 of pneumonia in bedridden individuals, many of whom have gastroesophageal reflux. CZP is a sedative and can cause behavior disturbances.

Testing 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].

Cystagon^TM has been used in the treatment of individuals with mutations in CLN1 [Zhang et al 2001; Wisniewski et al, personal observation].

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

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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).
• 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 [Wisniewski 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 new gene 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 affected or 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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is possible in pregnancies at 25% risk if biochemical studies in the proband have revealed deficient activity of the enzyme CTSD, PPT1, or the enzyme TPP-1, or if disease-causing mutations in any NCL genes 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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

Both human and animal forms of the disorders can be divided into two major groups, based on the nature of the material accumulated in lysosomes: 1) those characterized by the prominent storage of saposins (SAPs) A and D; and, 2) 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 is caused by the specific metabolic requirements of a neuron as a postmitotic cell or results 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 has nine exons spanning 25 kb.

Pathologic allelic variants. More than 40 mutations of PPT1 are known. The common mutations are p.Arg122Trp and p.Arg151X [Das et al 1998]; the others are uncommon or private mutations.

Normal gene product. PPT1 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. PPT1 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 PPT1 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 has 13 exons.

Pathologic allelic variants.: More than 50 mutations of TPP1 are known. The common mutations are p.Arg208X and c.509-1G>C [Zhong et al 1998, Sleat et al 1999]; the others are uncommon or private mutations.

Normal gene product. TPP-1 consists of 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 TPP1 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 contains 15 exons.

Pathologic allelic variants. More than 40 mutations are presently known. The common mutation is a c. 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 about 1-kb and includes exons 7 and 8. The genomic DNA designation is NG_008654.1:g.10373_11338del.

Normal gene product. The protein has 438 amino acids and 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].

CLN5

Normal allelic variants. The gene contains four exons.

Pathologic allelic variants. More than ten mutations are known. The first affected individuals were in Finland, but many cases have now been reported elsewhere. The mutation p.Tyr392X is observed in 94% of individuals with CLN5 who are of Finnish descent; the mutation p.Trp75X also segregates in affected individuals of Finnish descent. Other mutations are less common.

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

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

CLN6

Normal allelic variants. The gene has seven exons.

Pathologic allelic variants. Many mutations have been identified, including missense and nonsense mutations, small deletions or insertions, and splice site mutations. Affected individuals have been identified in many countries. The mutation p.Glu72X 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 8.

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 has 13 exons.

Pathologic allelic variants. Many mutations have been reported. Mutations in MFSD8 were originally identified in persons of Turkish origin. However, cases have now been described from many countries. 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 9.

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 has three exons.

Pathologic allelic variants. 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, has the allele-specific disease, Northern epilepsy/EPMR disease [Ranta et al 2001]. Other mutations in CLN8 give rise to the vLINCL phenotype.

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

Abnormal gene product. Unknown

CLN10

Normal allelic variants. The gene has nine exons.

Pathologic allelic variants. Only four mutations are known. None is common.

Normal gene product. Cathepsin D is an aspartate protease.

Abnormal gene product. Unknown

Literature Cited

1. Aberg L, Kirveskari E, Santavuori P. Lamotrigine therapy in juvenile neuronal ceroid lipofuscinosis. Epilepsia. 1999;40:796–9. [PubMed: 10368082]
2. Aberg LE, Backman M, Kirveskari E, Santavuori P. Epilepsy and antiepileptic drug therapy in juvenile neuronal ceroid lipofuscinosis. Epilepsia. 2000;41:1296–302. [PubMed: 11051125]
3. Backman ML, Santavuori PR, Aberg LE, Aronen ET. Psychiatric symptoms of children and adolescents with juvenile neuronal ceroid lipofuscinosis. J Intellect Disabil Res. 2005;49:25–32. [PubMed: 15634309]
4. Bellizzi JJ 3rd, Widom J, Kemp C, Lu JY, Das AK, Hofmann SL, Clardy J. The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis. Proc Natl Acad Sci U S A. 2000;97:4573–8. [PMC free article: PMC18274] [PubMed: 10781062]
5. Burneo JG, Arnold T, Palmer CA, Kuzniecky RI, Oh SJ, Faught E. Adult-onset neuronal ceroid lipofuscinosis (Kufs disease) with autosomal dominant inheritance in Alabama. Epilepsia. 2003;44:841–6. [PubMed: 12790899]
6. Crystal RG, Sondhi D, Hackett NR, Kaminsky SM, Worgall S, Stieg P, Souweidane M, Hosain S, Heier L, Ballon D, Dinner M, Wisniewski K, Kaplitt M, Greenwald BM, Howell JD, Strybing K, Dyke J, Voss H. Clinical protocol. Administration of a replication-deficient adeno-associated virus gene transfer vector expressing the human CLN2 cDNA to the brain of children with late infantile neuronal ceroid lipofuscinosis. Hum Gene Ther. 2004;15:1131–54. [PubMed: 15610613]
7. Das AK, Becerra CH, Yi W, Lu JY, Siakotos AN, Wisniewski KE, Hofmann SL. Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. J Clin Invest. 1998;102:361–70. [PMC free article: PMC508894] [PubMed: 9664077]
8. Gao H, Boustany RM, Espinola JA, Cotman SL, Srinidhi L, Antonellis KA, Gillis T, Qin X, Liu S, Donahue LR, Bronson RT, Faust JR, Stout D, Haines JL, Lerner TJ, MacDonald ME. Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet. 2002;70:324–35. [PMC free article: PMC384912] [PubMed: 11791207]
9. Hartikainen JM, Ju W, Wisniewski KE, Moroziewicz DN, Kaczmarski AL, McLendon L, Zhong D, Suarez CT, Brown WT, Zhong N. Late infantile neuronal ceroid lipofuscinosis is due to splicing mutations in the CLN2 gene. Mol Genet Metab. 1999;67:162–8. [PubMed: 10356316]
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Author Notes

The original author, Dr. Wisniewski, 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 17 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 Wisniewski, MD, PhD; New York State Institute for Basic Research in Developmental Disabilities (2001-2010)

Revision History

• 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