• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The TPP1 gene is associated with autosomal recessive neuronal ceroid lipofuscinosis type 2 (CLN2) (MedGen UID: 406281).

Pathogenic variants in the TPP1 gene are associated with ~97% of neuronal ceroid lipofuscinosis (NCL) type 2 (CLN2).

The cell is continually producing essential building blocks for life, such as proteins, metabolites, sugars, and lipids. These components are also continually degraded as they become damaged, overabundant, or unnecessary. If this balance is disrupted, then excess components can accumulate in the cell, interfering with normal function and causing toxicity. Defects in lysosomes, acidic cellular organelles that degrade cellular components, cause a group of conditions known as lysosomal storage disorders. The TPP1 gene, also called CLN2 in the literature, encodes a protein involved in endocytosis and cell death (PMID: 25962910).

OMIM: 204500

Clinical condition
TPP1 is the causative gene for most cases of the classic late-infantile form of NCL.

Patients with pathogenic variants in TPP1 usually present between 2 and 4 years of age with new onset seizures and other non-specific features including motor difficulties (ataxia) and language delay. Therefore, when patients initially present to clinic, CLN2 disease is not often suspected. Progression of CLN2 disease is often rapid (PMID: 22832778). Initial presentation is followed by loss of developmental milestones, with progressive psychomotor and cognitive decline. Patients often develop myoclonus and an ataxic gait that leaves them unable to walk. Progressive visual problems occur as the disease advances, resulting in blindness. (Saudubray; PMID: 22832778). Life expectancy is typically six years to early adolescence, although milder presentations with longer life expectancy have been reported (PMID: 20301601).

The most characteristic finding on electroencephalogram (EEG) is the finding of photoparoxysmal responses to low frequency (1-2 Hz) intermittent photic stimulation. However, this finding may be absent in some patients. Additional EEG findings can include slowing of background activity and epileptiform abnormalities in the posterior regions of the brain. Brain MRI may include progressive grey matter atrophy of the cerebellum and cerebrum and periventricular white matter hyperintensities (Reviewed in PMID: 27553878, 27445018).

CLN2 disease is one form of a group of heterogeneous NCLs with characteristic accumulation of ceroid lipopigments, mainly in neural tissues. Patients with CLN2 disease have deficient enzyme activity of tripeptidyl-peptidase 1 (TPP1). On histologic studies of lymphocytes, skin and conjunctival biopsies, electron microscopy show typical curvilinear bodies (CVB). Several forms of the NCLs show different enzymatic and patterns of histologic changes, although some other rare NCLs may also show CVB.

Many mutations in the TPP1 gene have been identified, including missense, nonsense, splice site, and small deletions/insertions. Estimated clinical sensitivity for identifying pathogenic variants in TPP1 is over 97% in children with CLN2 and tripeptidyl-peptidase 1 enzyme deficiency. Two mutations are common, c.509-1G>C and c.622C>T (p.Arg208X), although there are many rare private mutations reported as well (PMID: 9788728).

Due to the challenge of clinically diagnosing CLN2 disease in infants and young children with unexplained seizures, an international group of experts recommends the use of epilepsy gene panels, with confirmation of the diagnosis by tripeptidyl-peptidase 1 enzyme analysis or detection of 2 pathogenic variants (PMID: 27553878).

Differential diagnosis
Disorders presenting with seizures and developmental delay leading to loss of developmental milestones should be considered. These can include epileptic encephalopathies, other neuronal ceroid lipofuscinoses, lysosomal storage disorders, mitochondrial disorders, peroxisomal disorders, leukodystrophies. The differential diagnosis can also include a variety of seizure disorders including Rett syndrome, Dravet syndrome and progressive myoclonic epilepsy, which are addressed in the Invitae Epilepsy Panel.

Gene information
The TPP1 gene produces an enzyme called tripeptidyl peptidase 1. Deficiency of this enzyme prevents degradation of peptides, thereby leading to accumulation of certain proteins and other compounds in the lysosome. These accumulate as fatty substances called lipoproteins that build-up throughout the body and cause cell death in a range of tissues, especially in the neurons of the brain.

CLN2 disease shows autosomal recessive inheritance.

Treatment is symptomatic and palliative at present. Due to the challenges of treatment for the neurologic problems and other organ system involvement, multidisciplinary management is recommended.

Therapeutic clinical trials are ongoing and include recombinant TPP1 enzyme replacement therapy and gene transfer. A list of clinical trials is available at https://clinicaltrials.gov.

Review date: December 2016

Saudubray, JM, van den Berghe, G, Walter, JH (eds). Inborn Metabolic Diseases 5th edition Chap 39 571-577. Springer.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
CLN2 (TPP1) NM_000391.3