Symptom onset most commonly occurs in children aged 2-4 years, whereby the patients' prior development is normal. Affected children may present with seizures, delays in language development, motor difficulties, behavioral abnormalities, or dementia [1].

• Multiple seizure types are observed over the course of the disease, including myoclonic, tonic, tonic-clonic, atonic, and absence seizures. Myoclonic seizures may predominate as the disease progresses, and they may be accompanied by increasing clumsiness and ataxia. Electroencephalograms may reveal irregular activity, epileptiform abnormalities in posterior regions, and a slowing of background activity. Increased latency of visual evoked potentials may also be noted. If electroencephalograms are recorded with low-frequency intermittent photic stimulation (1-2 Hz), characteristic flash-per-flash responses may be seen [2].
• Beyond delays in the acquisition of language and motor facilities, patients with NCL type 2 show a rapid loss of previously attained skills. Language and motor function may decline to cero within 2-3 years after symptom onset, and this development is mirrored in progressive cerebellar and cerebral atrophy, reductions in grey matter volume, and periventricular white matter lesions [2].
• Neuronal loss implies a progressive loss of cognitive and visual function. Vision loss is not generally an early symptom but is usually observed from the second year of disease [3]. Accordingly, abnormalities revealed by electroretinograms and optical coherence tomography become more prominent during advanced stages of NCL type 2 [2].

• Inflammation

  One subject died 49 days postsurgery after developing status epilepticus on day 14, but with no evidence of CNS inflammation. Four of the 10 subjects developed a mild, mostly transient, humoral response to the vector. [ncbi.nlm.nih.gov]

• Pallor

  Some optic nerve pallor with attenuation of retinal vessels is also noted. B. Late phase FA of the right eye of patient 9 showing the “bull’s eye” maculopathy. C. [journals.plos.org]

  […] lipofucinosis (NCL) and represents a group of disorders that have a characteristic accumulation of liposfuscin in the neuronal tissues including the brain, retina and peripheral nerves. 2 The clinical ocular features of Batten disease include optic nerve pallor [reviewofoptometry.com]

• Retinal Pigmentation

  SD-OCT of patient 19 demonstrates considerable outer retinal atrophy with buildup of hyper-reflective material at the level of the retinal pigment epithelium. [journals.plos.org]

  Geographic atrophy of the retina and retinal pigment epithelium. d. Stabilization of acuity to 20/400. [reviewofoptometry.com]

• Torticollis

  Conversely, early developmental disturbances of vision often disrupt ocular motor control systems, giving rise to complex disorders such as nystagmus, strabismus, and torticollis. [books.google.com]

• Macula

  These outer retinal changes were also evident in OCT images performed outside the macula. [journals.plos.org]

• Apraxia

  Symptoms appear between ages 2 and 4 and consist of typical neurodegenerative complications: loss of muscle function (ataxia), drug resistant seizures (epilepsy), apraxia, development of muscle twitches (myoclonus), and vision impairment. [encyclopedia.uia.org]

  […] deficiency in tripeptidyl peptidase I as a result of a mutation in the TPP1 gene. [1] Symptoms appear between ages 2 and 4 and consist of typical neurodegenerative complications: loss of muscle function ( ataxia ), drug resistant seizures ( epilepsy ), apraxia [en.wikipedia.org]

• Gait Ataxia

  As the disease progressed, he developed progressive vision loss, gait ataxia, action myoclonus, and epilepsy. Electroencephalogram revealed generalized sharp and slow wave discharges with background slowing. [annalsofian.org]

  Clinically, NCLs cause a progressive delay in motor and mental milestones, leading to unsteadiness of gait, ataxia, epilepsy, and dementia. Retinal degeneration may lead to blindness. [mxe.eg.net]

• Neurologic Manifestation

  The ophthalmic evaluations were part of a thorough screening program of LINCL patients for inclusion in an on-going prospective NIH sponsored clinical trial of brain directed gene therapy for the treatment of neurological manifestations of LINCL ( www.clinicaltrials.gov [journals.plos.org]

• Motor Symptoms

  The disease initiated between four and a half and seven years with mental and slight motor symptoms. [ncbi.nlm.nih.gov]

Against the background of disease progression and irreversible neuronal damage, the timely diagnosis of NCL type 2 is gaining even more significance. Thus, when clinical signs and symptoms suggest any type of NCL, the measurement of tripeptidyl peptidase 1 activity should be among the first tests performed [2]. NCL type 2 should be suspected in all children presenting with new-onset unprovoked seizures, particularly when associated with a history of unexplained language delay and/or developmental milestone regression. Yet, similar observations may be made in patients with NCL type 1 and other types of NCL that may induce the late-infantile phenotype, namely types 5, 6, 7, and 8 [4].

NCL type 1 may be ruled out by assessing the activity of palmitoyl-protein thioesterase 1, which is unaltered in those suffering from NCL type 2. Residual enzyme activities can be assessed in dry blood spots, leukocytes, or fibroblasts. There are different methods with variable sensitivity: In the peripheral blood of patients with NCL type 2, residual tripeptidyl peptidase 1 activity averages 9%. In cultured fibroblasts, only 0.4% of normal levels are measured [4]. If enzyme activities cannot be determined or the respective tests yield inconclusive results, skin biopsy specimens or lymphocytes may be examined by electron microscopy for the presence of intracellular storage material [5].

The ultrastructural pattern of lysosomal autofluorescent lipopigments to be expected in samples obtained from patients with NCL type 2 is curvilinear. In the case of NCL type 1, there are granular osmiophilic deposits [4]. The detection of intracellular storage bodies, however, is insufficient for the diagnosis of a specific NCL disorder but should merely prompt genetic testing. Gene panels may be employed if doubts remain as to the underlying type of NCL. Otherwise, targeted molecular biological studies may be performed to identify the causative mutations in each allele of the TPP1 gene.

Of note, TPP1 mutations and subsequent deficiency of tripeptidyl peptidase 1 are not pathognomonic of NCL type 2 but may also be detected in autosomal recessive spinocerebellar ataxia type 7 (SCAR7). SCAR7 may be considered an atypical variant of NCL type 2 and manifests in ataxia, movement disorders, and cerebellar atrophy. Neither seizures nor visual impairment is typical of SCAR7, which is further characterized by its slowly progressive evolution until old age and the absence of ultrastructural curvilinear profiles [6].

• Generalized Sharp-and-Slow-Waves

  Electroencephalogram revealed generalized sharp and slow wave discharges with background slowing. [annalsofian.org]

In 2017, a milestone in the history of NCL treatment was reached with the approval of enzyme replacement therapy with recombinant human cerliponase alfa for the management of type 2 disease [7]. Cerliponase alfa therapy requires the surgical implantation of a reservoir and catheter to allow for the intracerebroventricular infusion of the proenzyme. 300 mg of the proenzyme are administered every other week. Hypersensitivity is common, but the production of drug-specific antibodies may be prevented by the application of antihistamines 30–60 minutes before the infusion. Neutralizing antibodies have not yet been detected in any patient treated with cerliponase alfa, and the development of antibodies is thus not predictive of a poor treatment outcome [3]. In sum, cerliponase alfa therapy is generally well tolerated. Adverse effects related to treatment are usually mild and comprise pyrexia, vomiting, and device-related infections.

NCL type 2 follows a largely predictable course with regard to the loss of language and motor function. According to retrospective studies, the median time between the onset of first symptoms and death was 7.8 years before the approval of cerliponase alfa therapy [1], and there are not yet any long-term studies regarding the development of patients who receive enzyme replacement therapy. In an open-label trial, a total of 23 patients were treated with cerliponase alfa for up to 240 weeks whereby the rate of psychomotor decline could be significantly reduced but not prevented. Loss of grey matter was still observed in all participants of the trial, totaling 6.7% per year [8]. Hence, it is to be expected that the life expectancy of patients with NCL type 2 remains below that of the general population even if enzyme replacement therapy is provided.

NCL type 2 is inherited in an autosomal recessive manner. The disease is caused by mutations of the TPP1 gene, which is located at 11p15.4 and encodes for the proteolytic enzyme tripeptidyl peptidase 1. This enzyme cleaves tripeptides from the N-termini of polypeptides that accumulate for degradation in the lysosome, whereby the precise substrates of tripeptidyl peptidase 1 remain unknown [3].

Mutations c.509-1G->A and c.622C->T account for more than half of all cases, but many more pathogenic variants of the TPP1 gene have been described. Homozygosity as well as compound heterozygosity have been related to the disease, and only 10-20% of all patients are negative for both of the aforementioned common alleles [1].

The overall incidence of NCL is often cited to be about 1 in 100,000 inhabitants, but national statistics range from 1 in 1,000,000 to 1 in 25,000 persons [9]. Highest rates are reported within the Scandinavian Peninsula, and in the western part of Finland, the local incidence of NCL may reach 1 in 1,500 people [4] [10]. In sum, data regarding the epidemiology of NCL are scarce, and information regarding the incidence and prevalence of its subtypes are even rarer. NCL type 2 is generally considered to be among the most common variants of the disease and may account for a considerable share of the aforementioned incidence, but geographic variations are to be expected. In Finland, for instance, late-infantile NCL is more likely to be due to type 5 than type 2 disease [10]. Turkish children with late-infantile NCL most often suffer from NCL type 7 [11].

NCL type 2 is caused by a deficiency of the lysosomal enzyme tripeptidyl peptidase 1. This leads to the accumulation of ceroid lipofuscin in many organs, including the central nervous system and retina. Degenerative changes are induced that reflect in progressive psychomotor decline [3]. A mechanistic explanation relating the built-up of lipopigments with neuronal degeneration has yet to be provided, but the level of storage burden is generally used as a readout of NCL progression and therapeutic efficacy [12]. Type 2 disease is no exception to this rule: Preclinical studies of cerliponase alfa therapy have confirmed the widespread distribution and uptake of the proenzyme, its intracellular activation, the clearance of lysosomal storage material and preservation of neuronal morphologic features [13]. At the same time, a reduction of neuroinflammation can be observed, suggesting the involvement of glial cells in the pathogenesis of NCL. This is indeed a paradigm shift since NCL has long since been defined as a neuronal disease - a new approach to NCL that offers the opportunity to identify further therapeutic targets and to develop more effective treatments [12].

Families known to harbor pathogenic TPP1 mutations should be offered genetic counseling. The prenatal diagnosis of NCL type 2 has long since been feasible and may help the parents to reach an informed decision. Beyond that, the identification of affected children before the onset of symptoms offers a major benefit in terms of treatment initiation. While it is not yet known whether the prophylactic administration of cerliponase alfa may prevent or delay the onset of symptoms in children with tripeptidyl peptidase 1 deficiency [8].

NCL is a general term referring to a heterogeneous group of lysosomal storage diseases, and the current classification scheme describes a total of 13 types [4] [5]. NCL type 2 is considered a variant of the late infantile form of type 1 and is often referred to as classical late-infantile NCL. It has been linked to mutations of the TPP1 gene which largely reduce the activity of the enzyme tripeptidyl peptidase 1. As a result, autofluorescent lipofuscin accumulates in the brain and many other organs, giving rise to seizures, cognitive and motor regression, vision loss, and ultimately death.

Fortunately though, cerliponase alfa could recently be approved as a drug that effectively attenuates the progression of NCL type 2. After intraventricular infusion, cerliponase alfa is uptaken by neurons, activated by the acidic environment in lysosomes, and capable of degrading those lipopigments that build up in the absence of tripeptidyl peptidase 1. Enzyme replacement therapy with recombinant human cerliponase alfa significantly improves the prognosis of children suffering from NCL type 2 and thus must definitely be considered a great success. Notwithstanding, further research is required to improve the effectivity of treatment, to be ultimately able not only to delay but to halt disease progression. Considerable efforts are currently undertaken to this end [12].

Neuronal ceroid lipofuscinosis (NCL) is a general term referring to a group of lysosomal storage diseases. These are hereditary metabolic disorders that imply the accumulation of non-degradable material in many organs, including the central nervous system and eye. Patients with NCL suffer from enzyme deficiencies, and NCL type 2 is related to the reduced activity of tripeptidyl peptidase 1. This enzyme is required for the degradation of certain polypeptides, and in its absence, those polypeptides build up in neurons and induce degenerative changes.

From a clinical point of view, NCL type 2 is characterized by seizures, the progressive impairment of motor skills, language deficiencies, cognitive regression, and blindness. Symptom onset typically occurs around the age of 3, and patients experience a rapid loss of previously acquired functions. The disease has been known to lead to death in early adolescence, but the availability of new therapies is likely to change that outcome: In 2017, enzyme replacement therapy with recombinant human cerliponase alfa has been approved for the management of NCL type 2. Cerliponase alfa is infused into the patient's brain through a catheter device that is surgically implanted under the child's scalp. It is widely distributed and uptaken by neurons, where it fulfills the function of tripeptidyl peptidase 1. Accumulated polypeptides are thus degraded and neuronal function can be preserved.

The rate of psychomotor decline can be reduced significantly with cerliponase alfa, although it is too early to make a long-term prognosis. Furthermore, neuronal damage sustained before the initiation of treatment may be irreversible, thus highlighting the need for a timely diagnosis. Genetic counseling may make an important contribution to this matter, as children carrying the causative mutations can be identified long before the onset of first symptoms.

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