Neuronal Ceroid Lipofuscinosis (Batten Disease)

The neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative, lysosomal storage disorders characterized by seizures, progressive cognitive and motor impairment, and vision loss. Also known as Batten disease, there are 14 types of NCL that have significant clinical overlap; genetic testing is often necessary to distinguish between them.

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The neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative, lysosomal storage disorders characterized by seizures, progressive cognitive and motor impairment, and vision loss. Also known as Batten disease, there are 14 types of NCL that have significant clinical overlap; genetic testing is often necessary to distinguish between them.

Disease Name 
Neuronal Ceroid Lipofuscinosis
Batten Disease
Disease Information 

All individuals with an NCL experience a progressive decline in cognition (dementia), accompanied by various motor function impairments.1 These often include spasticity, myoclonus in children, involuntary movements, and ataxia. Seizures are common and typically difficult to control. The combination of seizures and myoclonus in many children with an NCL can result in phenotypic overlap with progressive myoclonus epilepsy. Progressive vision loss occurs for most, but not all, individuals with an NCL.1

The NCLs are inherited in an autosomal recessive pattern, though adult-onset disease can be inherited either in an autosomal recessive or autosomal dominant pattern. NCLs are often classified by the age of onset of symptoms: infantile, late-infantile, juvenile, and adult. The use of genetic testing for NCL has revealed that multiple genes can be responsible for the same clinical presentation, thereby prompting a shift in nomenclature that includes both the causative gene and the age of onset:2,3

Type of NCL Reported Age of Onset Associated Gene
CLN1 Infantile: 6-24 months
Late-Infantile: 3-7.5 years
Adult: 15-50 years
PPT1
CLN2 *Late-Infantile: 2-4 years
Juvenile: 4-10 years
TPP1
CLN3 *Juvenile: 4-10 years
Adult: 15-50 years
CLN3
CLN4 Adult: 15-50 years DNAJC5
CLN5 Late-Infantile: 4-7 years
Adult: 15-50 years
CLN5
CLN6 Late-Infantile: 18 months – 8 years
Adult: 15-50 years
CLN6
CLN7 Late-Infantile MFSD8
CLN8 Late-Infantile: 3-7.5 years
Northern Epilepsy: 5-10 years
CLN8
CLN9 Juvenile: 4-10 years unknown
CLN10 Congenital: before or around birth
Late-Infantile
Adult: 15-50 years
CTSD
CLN11 Adult: 15-50 years GRN
CLN12 Juvenile ATP13A2
CLN13 Adult: 15-50 years CTSF
CLN14 Infantile KCTD7

*Most common NCLs

Initial evaluation of for an NCL can include enzyme assay, light microscopy (blood smear), and/or electron microscopy (skin biopsy or lymphocytes).1 Genetic testing is increasingly being used to confirm a diagnosis suggested by results from one of these testing methods, and in the setting of inconclusive results or atypical clinical presentations. Abnormal enzyme assay can be followed by single gene testing depending on the deficient enzyme:

Deficient Enzyme Gene to Test
Palmitoyl-protein thioesterase 1 (PPT-1) PPT1
Tripeptidyl peptidase 1 (TPP-1) TPP1
Cathepsin D (CTSD) CTSD

Additionally, light microscopy of a blood smear that reveals lymphocyte vacuoles suggests the diagnosis of CLN3, and subsequent genetic testing of CLN3 could be pursued to confirm this diagnosis. If initial evaluations do not support a specific NCL diagnosis, broader testing of multiple NCL genes can be helpful.

Testing Benefits & Indication 

Genetic testing is useful for diagnostic confirmation in symptomatic individuals and for testing of at-risk asymptomatic family members (including prenatal diagnosis). Molecular confirmation of a diagnosis may help avoid unnecessary testing and procedures, as well as guide recommendations for medical treatment.

Genetic testing may be considered for any of the following:

  • Newborns with seizures and microcephaly
  • Infants with seizures and developmental plateau or regression
  • School-age children with seizures and vision loss or cognitive decline
  • Individuals with a suspected NCL based on abnormal results from relevant enzyme assay or microscopy study
  • Any individual with a family history of NCL
  • Any individual with a clinical diagnosis of NCL interested in pursuing preimplantation genetic diagnosis or prenatal testing for NCL
Test Description 

NCLNext includes 13 genes known to be associated with the NCLs: ATP13A2, CLN3, CLN5, CLN6, CLN8, CTSD, CTSF, DNAJC5, GRN, KCTD7, MFSD8, PPT1, and TPP1. These genes are also included in our progressive myoclonus epilepsy panel (PMENext) and comprehensive epilepsy panel (EpilepsyNext). Single gene testing is available for PPT1, TPP1, CLN3, and CTSD. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, followed by polymerase chain reaction (PCR) and next generation sequencing (NGS).

Additional Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.4 This assay targets all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. Gross deletion/duplication analysis for available genes is performed utilizing a targeted chromosomal microarray. Specific mutation analysis is also available for individual mutations in genes on NCLNext that are known to be in the family.

Mutation Detection Rate 

NCLNext can detect >92% of the NCLs (clinical sensitivity).3 Our NCLNext panel can detect >99.9% of described mutations in these thirteen genes, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the Quick Links section at the top of this page.

Prenatal testing is available.

Turnaround Time 
TEST CODE TECHNIQUE TURNAROUND TIME
7025 NCLNext (13 genes, gene sequencing and deletion/duplication analysis) 4-6 weeks
7054 CLN3 gene sequencing and deletion/duplication analysis  2-4 weeks
7052 CTSD gene sequencing and deletion/duplication analysis  2-4 weeks
7050 PPT1 gene sequencing and deletion/duplication analysis 2-4 weeks
7051 TPP1 gene sequencing and deletion/duplication analysis  2-4 weeks

 

Specialty 
Genes 
ATP13A2
CLN5
CLN6
CLN8
CTSD
CTSF
DNAJC5
GRN
KCTD7
MFSD8
TPP1
References 
  1. Schulz A, et al. NCL diseases – clinical perspectives. Biochim Biophys Acta. 2013;1832(11):1801-1806.
  2. Haltia M and Goebel HH. The neuronal ceroid-lipofuscinoses: a historical introduction. Biochim Biophys Acta. 2013;1832(11):1795-1800.
  3. Mole SE and Williams RE. Neuronal Ceroid-Lipofuscinoses. October 10, 2001. [Updated August 1, 2013]. In: Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
  4. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.