Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis

Abstract

Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of lysosomal storage disorders. NCLs include the rare autosomal recessive neurodegenerative disorder neuronal ceroid lipofuscinosis type 2 (CLN2) disease, caused by mutations in the tripeptidyl peptidase 1 (TPP1)/CLN2 gene and the resulting TPP1 enzyme deficiency. CLN2 disease most commonly presents with seizures and/or ataxia in the late-infantile period (ages 2-4), often in combination with a history of language delay, followed by progressive childhood dementia, motor and visual deterioration, and early death. Atypical phenotypes are characterized by later onset and, in some instances, longer life expectancies. Early diagnosis is important to optimize clinical care and improve outcomes; however, currently, delays in diagnosis are common due to low disease awareness, nonspecific clinical presentation, and limited access to diagnostic testing in some regions. In May 2015, international experts met to recommend best laboratory practices for early diagnosis of CLN2 disease. When clinical signs suggest an NCL, TPP1 enzyme activity should be among the first tests performed (together with the palmitoyl-protein thioesterase enzyme activity assay to rule out CLN1 disease). However, reaching an initial suspicion of an NCL or CLN2 disease can be challenging; thus, use of an epilepsy gene panel for investigation of unexplained seizures in the late-infantile/childhood ages is encouraged. To confirm clinical suspicion of CLN2 disease, the recommended gold standard for laboratory diagnosis is demonstration of deficient TPP1 enzyme activity (in leukocytes, fibroblasts, or dried blood spots) and the identification of causative mutations in each allele of the TPP1/CLN2 gene. When it is not possible to perform both analyses, either demonstration of a) deficient TPP1 enzyme activity in leukocytes or fibroblasts, or b) detection of two pathogenic mutations in trans is diagnostic for CLN2 disease.

Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease

“…Historically, diagnoses of NCL subtypes have relied on histopathological techniques, such as an electron microscope evaluation of autofluorescent storage material morphology, together with a clinical review of disease onset and symptoms (Williams et al, ). Assaying of white blood cell TPP1 activity is now the mainstay of diagnosis for TPP1 ‐ related diseases (Fietz et al, ). Whereas this provides a direct test for CLN2 disease, it requires a specific suspicion of CLN2 or other NCL.…”

“…If patients have any indication of CLN2 disease, and molecular testing finds any pathogenic or likely pathogenic variant in TPP1 , TPP1 enzyme activity testing can be used to confirm the diagnosis. In addition, if a second variant is not identified, but enzyme activity is deficient, this can be used as evidence to classify any other potentially deleterious variants in the patient as well as provide a laboratory‐based diagnosis of CLN2 disease (Fietz et al, ; Richards et al, ).…”

“…On a regional level, these variants appeared less frequently outside Europe and North America ( Figure 3). The allele c.851 G>T (p.(Gly284Val)), originally identified in Newfoundland, was the second most common allele in North America and is a wellcharacterized founder effect mutation in classic late-infantile CLN2 disease (Fietz et al, 2016) (Lin, Sohar, Lackland, & Lobel, 2001;Pal et al, 2009). In vivo substrates of TPP1 are not well characterized and the pathological mechanisms underlying the disease remain unclear (Cooper, Tarczyluk, & Nelvagal, 2015;Palmer, Barry, Tyynelä, & Cooper, 2013;Stumpf et al, 2017).…”

“…To date, mutations in 13 human genes have been linked with NCL disorders (Mole, ). Classic late‐infantile neuronal ceroid lipofuscinosis, CLN2 disease, is the result of tripeptidyl peptidase I (TPP1) deficiency, caused by autosomal recessive inheritance of two pathogenic variants in trans in the TPP1 (MIM# 607998, CLN2) gene (Fietz et al, ; Mole, Gardner, Schulz, & Xin, ; Sleat et al, ).…”

Photosensitivity is an early marker of neuronal ceroid lipofuscinosis type 2 disease

“…Separate trains of flashes of 5-s duration were used at the following frequencies: 1, 2, 6,8,10,12,13,14,15,16,17,18,19,20,25,30,40,50, and 60 Hz. The international 10-20 system of electrode placement was used to record EEGs.…”