Clinical 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 pathogenic variants 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. Pathogenic variants 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 older than 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 mutated 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 pathogenic variants 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 pathogenic variant(s) have been identified in the family.

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 pathogenic variants in many, if not all, NCL-associated genes may result in a milder or more severe disease phenotype.

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 pathogenic variants [Voznyi et al 1999].
• Tripeptidyl-peptidase 1 (TPP-1) encoded by TPP1. Individuals with TPP1 pathogenic variants 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 pathogenic variants usually have significantly reduced enzymatic activity in leukocytes or fibroblasts.

A carrier of a pathogenic variant 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].

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.

Carrier testing for relatives at risk for the autosomal recessive forms of NCL requires prior identification of the pathogenic variants 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 pathogenic variant(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, allelic variants, 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 pathogenic variants 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

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 pathogenic variants 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].

Genotype-Phenotype Correlations

Mutation of 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].

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].

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
• Clinical 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 pathogenic variants 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 pathogenic variants 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 in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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.

Autosomal Recessive Inheritance

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

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 pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.
• If the pathogenic variant 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 pathogenic variant 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 pathogenic variant include molecular genetic testing of the identified variant. 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 pathogenic variant 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 pathogenic variant.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

If biochemical studies in the proband have revealed deficient activity of the enzyme CTSD, PPT-1, or the enzyme TPP-1, or if the pathogenic variant(s) have been identified in the proband and parents, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Molecular 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 pathogenic variants present in NCL is listed in the NCL Mutation Database www.ucl.ac.uk/ncl (see also Table A).

For a detailed summary of gene and protein information for the genes associated with NCLs, see Table A, Gene.

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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 more than 300 publications and numerous books and book chapters in the field of progressive neurogenetic diseases and intellectual and developmental disabilities. Dr Wiśniewski died of complications of cancer on May 30, 2008.

Current author Sara Mole, PhD is a research scientist with more than 20 years' experience in the neuronal ceroid lipofuscinoses. She curates the NCL Mutation Database, part of the NCL Resource website, and is an author of many scientific articles, reviews, and book chapters, as well as 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 (2001-2008)

Revision History

• 11 April 2019 (ma) Chapter retired: Chapter does not reflect current use of genetic testing.
• 1 August 2013 (me) Comprehensive update posted live
• 2 March 2010 (me) Comprehensive update posted live
• 17 May 2006 (me) Comprehensive update posted live
• 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 live
• 12 June 2003 (kw) Revision: testing
• 10 October 2001 (me) Review posted live
• 20 February 2001 (kw) Original submission