O slideshow foi denunciado.
Utilizamos seu perfil e dados de atividades no LinkedIn para personalizar e exibir anúncios mais relevantes. Altere suas preferências de anúncios quando desejar.

BDSRA 2015 CLN2 Schulz, Miller, Mole, Cohen

2015 CLN2 Schulz, Miller, Mole, Cohen

  • Entre para ver os comentários

  • Seja a primeira pessoa a gostar disto

BDSRA 2015 CLN2 Schulz, Miller, Mole, Cohen

  1. 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