Neuronal Ceriod Lipofuscinosis-2 (CLN) disorder, a type of Batten disease caused by TPP1 enzyme deficiency: Current knowledge of the natural history from international experts

1. Neuronal Ceroid Lipofuscinosis-2 (CLN2) disorder, a type of Batten disease caused by TPP1 enzyme deficiency:
Current knowledge of the natural history from international experts
Ruth E. Williams1
, Jessica L. Cohen-Pfeffer2
, Ronald Crystal3
, Emily de los Reyes4
, Yoshikatsu Eto5
, Norberto Guelbert6
, Bénédicte Héron7
, Svetlana Mikhailova8
, Nicole Miller2
,
Jonathan W. Mink9
, Maria Socorro Pérez-Poyato10
, Alessandro Simonati11
, Katherine Sims12
, Angela Schulz13
1
Children’s Neurosciences, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2
BioMarin Pharmaceutical Inc., Novato, CA, USA; 3
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA; 4
Department of Pediatric Neurology, Nationwide Children’s
Hospital, Columbus, OH, USA; 5
Advanced Clinical Research Center, Southern Tohoku Brain Research Center, Kawasaki, Japan; 6
Hospital de Niños de Cordoba, Cordoba, Argentina; 7
Service de Neuropédiatrie, CHU Paris Est – Hôpital d’Enfants Armand-Trousseau, Paris, France;
8
Department of Medical Genetics, Russian Pediatric Regional Hospital, Moscow, Russia; 9
Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA; 10
Unit of Pediatric Neurology, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain;
11
Department of Neurological and Movement Sciences-Neurology, University of Verona, Verona, Italy; 12
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; 13
Department of Paediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Results
Background
■■ The neuronal ceroid lipofuscinoses (NCLs) are the most common cause 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 thought to be ~ 0.5 per 100,000 live births5
, but CLN2
disorder is believed to be underdiagnosed
■■ Treatment is currently symptomatic, 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. The data were discussed at a subsequent meeting.
©2016 BioMarin Pharmaceutical Inc. All rights reserved.Presented at the British Paediatric Neurology Association (BPNA) - 42nd Annual Conference, 27-29 January, 2016, Sheffield, United Kingdom
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 (see poster P-565)
■■ 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
Table 1. Biochemical and molecular genetic diagnostic tests for CLN2
TPP1 enzyme deficiency Molecular testing
■■ Leukocytes
■■ Fibroblasts
■■ Dried blood spot
■■ Two pathogenic mutations in CLN2/TPP1
gene
■■ NCL mutation and patient database:
http://www.ucl.ac.uk/ncl/mutation.shtml
Conclusions
■■ These data are based on expert opinion collected from a survey and meeting
■■ CLN2 is a severe, progressive, pediatric-onset neurodegenerative disorder
■■ Epilepsy seems polymorphic with predominant generalized seizures and high
frequency of myoclonic manifestations
■■ Seizures with history of language delay and decline should raise suspicion of
CLN2 disease6
■■ Disease awareness is low among non-expert clinicians, resulting in delays in
diagnosis and referrals
■■ 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 (see poster P-565)
■■ Knowledge of CLN2 is paramount to ensure timely diagnosis and to enable
early initiation of future therapies
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
Age of onset
■■ Symptom onset typically occurs between 1.5-5 years of age, but may occur later
(9-12 years)
Figure 1. Expert opinion on 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
Seizures
■■ Seizures have been recognized as the first symptom as this manifestation brings
an affected child to medical attention
■■ Myoclonic seizures were the most commonly reported seizure type, but other types
are common
Acknowledgments:
BioMarin Pharmaceutical Inc. sponsored this meeting and survey. The authors thank all survey and meeting
participants: Jonathan Cooper (King’s College, London, UK), Michael Fietz (SA Pathology, North Adelaide,
Australia), Alfried Kohlschütter (University Medical Center Hamburg-Eppendorf, Hamburg, Germany), Charles
Marques Lourenço (University of São Paulo, Brazil), David A. Pearce (Sanford Children’s Health Research
Center, South Dakota, USA), Zoltan Lukacs (University Medical Center Hamburg-Eppendorf, Hamburg,
Germany), Sara Mole (University College, London, UK), and Inés Noher de Halac (Universidad Nacional de
Cordoba, Argentina).
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 ketogenic diet has a place for seizure control in these children
Figure 3. Types of seizures in CLN2Figure 2. CLN2 initial presenting symptoms
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.
6. Nickel et al. Late language acquisition and unexplained epilepsy are indicators of easily detectable CLN2 disease. Eur J Paediatr Neurol. 2015; 19: S38.
http://www.bmrn.com/pdf/BPNA2016p1.pdf
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