1) The document summarizes the findings of an international survey of CLN2 experts regarding the natural history, diagnosis and management of CLN2 disease. 2) CLN2 disease is a rare, fatal pediatric neurological disorder caused by TPP1 enzyme deficiency. Initial symptoms typically include seizures, speech/language delays, and developmental regression between 1.5-5 years of age. 3) The survey found delays of 1-4 years between first symptoms and CLN2 diagnosis due to low disease awareness. Timely diagnosis is important to enable future treatment options.

1. Presented at the Batten Disease Support and Research Association (BDSRA) 2015 Annual Family Conference Meeting ©2015 BioMarin Pharmaceutical Inc. All rights reserved.
Neuronal Ceroid Lipofuscinosis-2 (CLN2) natural history and path to diagnosis: International experts’ current experience
and recommendations on CLN2 disease, a type of Batten disease, resulting from TPP1 enzyme deficiency
Angela Schulz*1
, Nicole Miller*2
, Sara E Mole3
, Jessica L Cohen-Pfeffer2
(*co-first authors)
1
Department of Paediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2
BioMarin Pharmaceutical Inc., Novato, CA, USA 3
MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
Other clinical signs and symptoms
■■ Sleep abnormalities were reported by all expert
clinicians
■■ Visual impairment was reported to arise at a
mean age of 3.5 years (range = 1-9 years) and
progresses to blindness by a mean age of 7.1
years (range = 2-10 years)
■■ Anxiety was identified as a common symptom
■■ Due to neurodegeneration and subsequent
immobility, secondary complications in the
following systems were reported: respiratory,
gastrointestinal, skeletal, muscular, immune and
endocrine
■■ Cardiac rhythm anomalies, not previously
associated with CLN2, were also reported
Management
■■ Use of antiepileptic drugs, gastric feeding
tubes, and physical/occupational therapy were
identified as the most impactful strategies in
managing patients
■■ Notably, seizures are refractory, oftentimes
requiring polytherapy
–– Valproic acid is commonly used in combination
with 1 or 2 other anti-epileptic medications such
as lamotrigine, levetiracetam, zonisamide, and a
benzodiazepine like clobazam, clonazepam and
diazepam
–– Some experts stated that diet has a place for
seizure control in these children
Delays in diagnosis
■■ A 1-4 year delay was reported between first
onset of symptoms and diagnosis
■■ Delays in clinical suspicion and referral and a
lack of awareness of available diagnostic tests
were identified as the most significant barriers to
timely diagnosis
■■ CLN2 is most commonly diagnosed by
neurologists/pediatric neurologists,
metabolic specialists/geneticists, and pediatric
epileptologists
Figure 4. Time from onset of symptoms to specialist referral
and diagnosis of CLN2
Diagnosing CLN2
■■ Most experts perform either a TPP1 enzyme
activity test and/or a molecular test to confirm a
diagnosis of CLN2
■■ Electron microscopy is performed in some parts
of the world in suspected cases
■■ Clinical tests including brain magnetic
resonance imaging (MRI), visual evoked
potentials (VEP) and electroencephalography
(EEG) may also be performed when CLN2 is
suspected
Figure 5. Biochemical and molecular genetic diagnostic
tests for CLN2
Conclusions
■■ CLN2 is a severe, progressive, pediatric-onset
neurodegenerative disorder
■■ Disease awareness is low among non-expert
clinicians, resulting in delays in diagnosis and
referrals
■■ Seizures in concert with a regression of
language and/or motor milestones should raise
suspicion for CLN2
■■ The gold standard for diagnosis of CLN2 is
demonstration of decreased TPP1 enzyme
activity and/or detection of two pathogenic
mutations in the CLN2/TPP1 gene
■■ Knowledge of CLN2 is paramount to ensure
timely diagnosis and to enable early initiation of
future therapies
Age of onset
■■ Symptom onset typically occurs between 1.5-5
years of age, but may occur later (9-12 years)
Figure 1. Variation in the age of onset of CLN2 symptoms
Initial presenting symptoms
■■ Seizures/epilepsy, speech delay/decline and
developmental delay/regression were reported as
the most common initial presenting symptoms
Figure 2. CLN2 initial presenting symptoms
Seizures
■■ Seizures have been recognized as the first
symptom as this manifestation brings an affected
child to medical attention
■■ Myoclonic epilepsy was the most commonly
reported seizure type, but other types are common
Figure 3. Types of seizures in CLN2
14
12
10
8
6
4
2
0
Ageofonset,
range(years)
Respondents
0
n=14
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Range in Age of Onset
TPP1 enzyme deficiency Molecular testing
■■ Leukocytes
■■ Fibroblasts
■■ Dried blood spot
■■ 2 pathogenic mutations in
CLN2/TPP1 gene
■■ NCL mutation and patient
database:
http://www.ucl.ac.uk/ncl/mutation.shtml
References:
1. Schulz A et al. NCL diseases – clinical perspectives. Biochim Biophys Acta 2013; 1832:1801-6.
2. Mole SE, et al. The Neuronal Ceroid Lipofuscinoses (Batten Disease). 2 ed. Oxford, UK: Oxford
University Press; 2011.
3. Steinfeld et al. Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical
course in patients with CLN2 mutations.
Am J Med Genet. 2002;112:347-54.
4. Worgall S et al. Neurological deterioration in late infantile neuronal ceroid lipofuscinosis. Neurology.
2007;69:521-35
5. Claussen et al. Incidence of neuronal ceroid-lipofuscinoses in West Germany: variation of a method
for studying autosomal recessive disorders. Am J Med Genet. 1992; 42:536-8.
Acknowledgments:
The authors thank all survey participants: Jonathan Cooper (King’s College, London, UK), Ronald
Crystal (Weill Cornell Medical College, NY, USA), Emily de los Reyes (Nationwide Children’s Hospital,
OH, USA), Yoshikatsu Eto (Southern Tohoku Brain Research Center, Kawasaki, Japan), Michael Fietz
(SA Pathology, North Adelaide, Australia), Norberto Guelbert (Hospital de Niños de Cordoba, Argenti-
na), Inés Noher de Halac (Universidad Nacional de Cordoba, Argentina), Bénédicte Héron (CHU Paris
Est – Hôpital d’Enfants Armand-Trousseau, Paris, France), Zoltan Lukacs (University Medical Center
Hamburg-Eppendorf, Germany), Svetlana Mikhailova (Russian Pediatric Regional Hospital, Moscow,
Russia), Jonathan Mink (University of Rochester Medical Center, NY, USA), David A. Pearce (Sanford
Children’s Health Research Center, SD, USA), María Socorro Pérez Poyato (Hospital Universitario
Marqués de Valdecilla, Santander, Cantabria, Spain), Alessandro Simonati (University of Verona, Italy),
Katherine Sims (Massachusetts General Hospital, MA, USA) and Ruth Williams (Guy’s and St Thomas’
NHS Foundation Trust, London, UK).
Background
■■ The neuronal ceroid lipofuscinoses
(NCLs) are the most common group of
neurodegenerative disorders in children and
adolescents1,2
■■ CLN2 disorder, a type of NCL, is an ultra-
rare pediatric-onset lysosomal storage
disease caused by tripeptidyl peptidase 1
(TPP1) enzyme deficiency1-4
■■ CLN2 is characterized by language delay,
seizures, progressive dementia,
motor and visual deterioration, and early
death1-4
■■ Worldwide incidence is ~ 0.5 per 100,000
live births5
, but CLN2 disorder
is believed to be underdiagnosed
■■ Treatment is currently supportive and
palliative only
Objectives
■■ To describe current practices and challenges
related to diagnosis and natural history of
CLN2 disease
Methods
■■ Between September and October 2014, 22
clinicians, academic researchers and laboratory
directors from around the world with extensive
experience in managing and/or diagnosing
NCLs were invited to complete an online survey
comprising questions on the presentation,
natural history, diagnosis and management of
CLN2
Results
Survey respondents
■■ 18 NCL experts from 10 countries
completed the survey
–– 6 pediatric neurologists, 3 neurologists,
3 metabolic specialists/geneticists,
1 pediatrician, 1 clinical geneticist, 2
biochemical genetics laboratory directors, 2
research scientists
–– Survey respondents were from the USA,
Argentina, Germany, the UK, France, Italy,
Spain, Russia, Australia, and Japan
Monthsn=12 *mean
0 10 20 30
23.6*
40 50
Time from Onset of Symptoms to:
Referral to
NCL Specialist
Diagnosis
21.7*
Number of Responsesn=17
0 2 4 6 8 10 12 14 16
Epilepsy/Seizures
Speech/Language Decline
Developmental Delay/Regression
Psychomotor Decline
Ataxia
Myoclonus
Visual Deterioration
Number of Responses
0
n=11
2 4 6 8 10 12
Generalized: Myoclonic
Generalized: Tonic-clonic (grand mal)
Partial: Complex partial
Generalized: Atonic/Drop attacks
Status epilepticus
Partial: Partial seizures
that become generalized
Generalized: Absence (petit mal)
Partial: Simple partial
Generalized: Clonic
Generalized: Tonic