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A literature review focused on childhood onset NCL Childhood
Early signs and symptoms of Neuronal Ceroid Lipofuscinosis (NCL)
Alanna Gayko, MEd, (MPhil Candidature); Dr Elizabeth Kepreotes PhD; Dr Tracy Dudding-Byth BMed, FRACP, PhD; Professor Vanessa McDonald PhD
Faculty of Health and Medicine, School of Nursing and Midwifery, University of Newcastle, Australia
Delayed or initial misdiagnosis of NCL (Batten disease) is
experienced by many families. NCL affects all age groups, but
predominantly young children.
Our aim was to undertake a comprehensive literature review to
establish the known early signs and symptoms of childhood onset
NCL. The focus was on the early pre-diagnostic phase.
The PubMed® database was searched for articles which referred
to early symptoms of any subtype of NCL. The MESH terms
‘Neuronal Ceroid Lipofuscinosis’ AND ‘symptoms’ were used.
Google Scholar was manually searched using the eponym Batten
disease and the CLN1-14 subtypes.
1,193 articles were identified during this review completed on June
30th, 2018. Duplicates and articles not specifying early onset NCL
symptoms in childhood were excluded. This is an excerpt of the
130 historical and recent articles included in the literature review.
From the literature review we identified symptoms specific to each
subtype and the age of onset. Factors are identifiable which
facilitate or delay diagnosis of childhood onset NCL.
Paramount symptoms: NCL is the leading life-limiting Mendelian
cause of neurodegeneration and dementia in children . Stalling
and regression of psychomotor abilities in a young child is the broad
symptom heralding the onset of dementia requiring consideration of
NCL. Symptoms such as speech delay or regression, ataxia, onset
of seizures, and visual loss are characteristic of specific subtypes. A
child has usually achieved normal developmental milestones .
Age of onset: With exceptions of later onset phenotypes and rarer
subtypes, the age of childhood onset NCL subtypes is narrow. The
earliest onset subtypes are congenital-CLN10 (perinatal to
postnatal) and during infancy-CLN1 (six months to two years).
Children have an onset in the late infantile period-CLN2 (two to four
years). Slightly older children with the juvenile onset-CNL3 become
symptomatic (between four and seven years, or later) [3, 18].
Variants CLN5-CLN8 may present at two to five years or older [6-9].
Health professionals: Speech pathologists (CLN2)  and
ophthalmologists (CLN3)  may review these children in the early
symptomatic, but pre-diagnostic phase of NCL. Tailoring education
and awareness of NCL can reduce time to diagnosis of NCL .
Differential diagnosis: CLN2 may be initially misdiagnosed as
epilepsy syndromes . Initial ophthalmology misdiagnoses are
common for several subtypes, but particularly CLN3 [20, 22].
Benefits of early diagnosis: To end a protracted diagnostic
journey, sometimes referred to as a ‘diagnostic odyssey’ in rare
disease literature. Delayed diagnosis may be:
• ˃ 21 months for CLN2, late-infantile [3-4]
• ˃ two years for CNL3, juvenile 
Emerging treatments: Early diagnosis of NCL may facilitate
participation in a clinical trial . It could expedite access to the
first disease modifying treatment for children with a genetic
diagnosis of CLN2  or other emerging treatments .
NCL is typified by misdiagnosis or a delayed diagnosis. Identifying
dementia in childhood is protracted as symptoms merge with more
common or other rare diseases. The interval from subtle symptoms
- a prodromal phase - before overt symptoms and diagnosis may
illuminate the onset of NCL. Parents are well equipped to identify
distinctive features of this pre-diagnostic period in their child or
children. Symptom onset and the diagnostic experience of families
will be retrospectively explored in a forthcoming Australian study.
1. van Ruiten, H.J., et al., Improving recognition of Duchenne muscular dystrophy: a retrospective case note review. Archives of disease in childhood, 2014. 99(12): p. 1074-1077.
2. Schulz, A. and A. Kohlschutter, NCL Disorders: frequent causes of childhood dementia. Iranian journal of child neurology, 2013. 7(1): p. 1-8.
3. Williams, R.E., et al., Diagnosis of the neuronal ceroid lipofuscinoses: an update. Biochim Biophys Acta, 2006. 1762(10): p. 865-72.
4. Fietz, M .., et al., Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis. Molecular Genetics and Metabolism, 2016. 119(1): p. 160-167.
5. Adams, H.R., J.W. Mink, and the University of Rochester Batten Center Study Group, Neurobehavioral features and natural history of juvenile neuronal ceroid lipofuscinosis (Batten disease). J Child Neurol, 2013. 28(9): p. 1128-36.
6. Simonati, A., et al., Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5. Dev Med Child Neurol, 2017. 59(8): p. 815-821.
7. Canafoglia, L., et al., Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations. Neurology, 2015. 85(4): p. 316-324.
8. Aiello, C., et al., Mutations in MFSD8/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis. Hum Mutat, 2009. 30(3): p. E530-40.
9. Striano, P., et al., Clinical and electrophysiological features of epilepsy in Italian patients with CLN8 mutations. Epilepsy Behav, 2007. 10(1): p. 187-91.
10. Santavuori, P., S.-L. Vanhanen, and T. Autti, Clinical and neuroradiological diagnostic aspects of neuronal ceroid lipofuscinoses disorders. European Journal of Paediatric Neurology, 2001. 5: p. 157-161.
11. Williams, R.E., S. Boyd, and B.D. Lake, Ultrastructural and electrophysiological correlation of the genotypes of NCL. Molecular genetics and metabolism, 1999. 66(4): p. 398-400.
12. Siintola, E., et al., Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain, 2006. 129(6): p. 1438-1445.
Acknowledgements: This research is partly supported by an Australian Government Research Training Program Scholarship
The most common age of childhood onset subtypes is between two and five years [2-9] as provided in
Figure 1. CLN1 has an infantile onset between 6 months to two years  and CLN10 has a
congenital onset , or later.
Figure 1: Ages of neonatal and childhood onset subtypes CLN 10, 1-3 and 5-8
Early signs and symptoms of childhood onset NCL subtypes were
identified in the literature. The mnemonic NEURONS has been
used , to summarise the distinctive features of these NCL
subtypes. Table 1 below focuses on the earliest symptoms of
neurological standstill, then regression in a young infant or child.
These can range from subtle to obvious changes to speech, gait
(ataxia), and behaviour prior to seizures (CLN2), visual loss
(CLN3) [2-5] and initial symptoms of other subtypes [6-10].
Enlarged organs (organomegaly) or distinctive facial features
(dysmorphia) are not characteristic of early NCL [15,4].
Ultrastructural pathology is distinctive to NCL, but vacuolated
lymphocytes identified in CLN3 are also found in other lysosomal
Table 1: Distinctive features of childhood onset NCL
phenotypes of CLN1-3 [2-5], CLN5-8 [6-10]
Facilitators and hindrances of NCL diagnosis are
outlined in the adjoining Figure 2.
Facilitators of diagnosis:
1. Parents (and others) may identify early subtle
symptoms in their child or children 
2. Consideration of NCL by the medical
practitioner (and other professionals) [4, 14]
3. Family and medical history → referral [4, 22]
Hindrances of diagnosis:
4. Lack of awareness of NCL [2, 21]
5. Subtle symptoms prior to motor or visual ↓ 
6. No facial dysmorphia or organomegaly [4, 15]
7. Differential diagnoses: Rett syndrome CLN1, 2
, retinitis pigmentosa CLN3 
Figure 2: Facilitators and hindrances of
The earliest symptoms of the CLN1-CLN3 subtypes are provided in Figure 3 [4-5, 10, 16-17]. Speech
delay/regression can be identified early in CLN5-CLN6 [6-7], and clumsiness at the onset of CLN5 .
Figure 3: Early presentation of childhood onset phenotypes of CLN1-CLN3
Signs & symptoms of childhood onset NCL Subtypes
1. N: Neurological standstill CLN1, 2
2. E: Epilepsy - Tonic-clonic, myoclonus CLN2, 7, 8
3. U: Ultrastructural pathology, autofluorescence All subtypes 
4. R: Regression - motor/cognitive, dementia CLN1, 2, 3
5. O: Ophthalmic - retinopathy, vision loss CLN3
6. N: New onset ataxia CLN1, 2, 6
7. S: Speech delay CLN1, 2, 5, 6
13. Pampiglione, G. and A. Harden, So-called neuronal lipofuscinosis. Neurological studies in 60 children. Journal of Neurology, Neurosurgery, and Psychiatry., 1977. 40: p. 323-330.
14. Puga, A.C.S., et al., Neuronal ceroid lipofuscinoses: a clinical and morphological study of 17 patients from southern Brazil. Arquivos de neuro-psiquiatria, 2000. 58(3A): p. 597-606.
15. Gilbert-Barness, E. and P.M. Farrell, Approach to diagnosis of metabolic diseases. Translational Science of Rare Diseases, 2016. 1(1): p. 3-22.
16. Kuper, W.F., et al., Timing of cognitive decline in CLN3 disease. Journal of inherited metabolic disease, 2018: p. 1-5.
17. Nickel, M., A. Kohlschütter, and A. Schulz, Late Talkers in Late Infantile CLN2 Disease: Red Flag for an Early Diagnosis. Neuropediatrics, 2015. 46(S 01): p. PS01-20.
18. Nita, D.A., S.E. Mole, and B.A. Minassian, Neuronal ceroid lipofuscinoses. Epileptic Disord, 2016. 18(S2): p. 73-88.
19. Mole, S.E., R.E. Williams, and H.H. Goebel, Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics, 2005. 6(3): p. 107-126.
20. Dulz, S., et al., Novel morphological macular findings in juvenile CLN3 disease. Br J Ophthalmol, 2016. 100(6): p. 824-8.
21. Cismondi, I.A., et al., Guidelines for incorporating scientific knowledge and practice on rare diseases into higher education: neuronal ceroid lipofuscinoses as a model disorder. Biochim Biophys Acta, 2015. 1852(10 Pt B): p. 2316-23.
22. Collins, J., et al., Batten disease: features to facilitate early diagnosis. Br J Ophthalmol, 2006. 90(9): p. 1119-24.
23. Velinov, M., Neuronal Ceroid Lipofuscinoses: Why early diagnosis matters? Ann Pediatr Child Health, 2014. 2(2)(1016): p. 1-3.
24. Schulz, A., et al., Long-term safety and efficacy of intracerebroventricular enzyme replacement therapy with cerliponase alfa in children with CLN2 disease: Two year results from an ongoing multicenter extension study.
Molecular Genetics and Metabolism, 2018. 123(2): p. S126-S127.
25. www.clinicaltrials.org Accessed on 30th June 2018.