Study of Intraventricular Cerliponase Alfa for CLN2 Disease

Schulz, Angela; Ajayi, Temitayo; Specchio, Nicola; Reyes, Emily de los; Gissen, Paul; Ballon, Douglas; Dyke, Jonathan P.; Cahan, Heather; Slasor, Peter; Jacoby, David; Kohlschütter, Alfried

doi:10.1056/nejmoa1712649

Cited by 381 publications

(427 citation statements)

References 15 publications

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“…[181][182][183] With the advent of next generation sequencing and enhanced clinical phenotyping, it is likely that the genetic epilepsy-dyskinesia spectrum will further expand. These disorders are often under-recognized, mainly because of their rarity and heterogeneity, and, therefore, delays in diagnosis and appropriate management are common.…”

Section: Discussionmentioning

confidence: 99%

The expanding spectrum of movement disorders in genetic epilepsies

Papandreou

Danti

Spaull

et al. 2019

Develop Med Child Neuro

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An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. What this paper adds Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required.

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Section: Discussionmentioning

confidence: 99%

The expanding spectrum of movement disorders in genetic epilepsies

Papandreou

Danti

Spaull

et al. 2019

Develop Med Child Neuro

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“…Finally, Batten disease or neuronal ceroid lipofuscinosis, estimated to affect only about 50 children per year in the United States, now has a Food and Drug Administration (FDA)–approved therapy. Its availability has spurred efforts to diagnose affected children at the time of the first presentation with epilepsy before all of the features of the disease are apparent, obtain a genetic diagnosis, and proceed to therapy immediately …”

Section: Discussionmentioning

confidence: 99%

Evolution and course of early life developmental encephalopathic epilepsies: Focus on Lennox‐Gastaut syndrome

2018

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Objectives: Developmental encephalopathic epilepsies (DEE) are characterized by refractory seizures, disability, and early death. Opportunities to improve care and outcomes focus on West Syndrome/infantile spasms (WS/IS). Lennox-Gastaut syndrome (LGS) is almost as common but receives little attention. We examined initial presentations of DEEs and their evolution over time to identify risk and indicators of developing LGS. Methods: Data are from the Connecticut Study of Epilepsy, a prospective, longitudinal study of 613 children with newly-diagnosed epilepsy recruited in 1993–1997. Central review of medical records permitted classification of epilepsy syndromes at diagnosis and reclassification 2, 5, and 9 years later. DEEs were compared to other epilepsies for seizure and cognitive outcomes, and mortality. Analyses examined the evolution of DEE syndromes after initial presentation with specific comparisons made between WS/IS and LGS. Statistical analyses were performed with t-tests and chi-squares. Results: Fifty-eight (9.4%) had DEEs, median onset age=1.1y (interquartile range (IQR)= 0.3, 1.3) in DEEs and 6.0y (IQR=3.0, 9.0) in other epilepsies (p<0.001). DEEs versus other epilepsies had more pharmacoresistance (71% versus 18%), intellectual disability (84% versus 11%), and mortality (21% versus <1%; all p<0.001). During follow-up, the form of epilepsy evolved in 33 children. WS/IS was the most common initial diagnosis (N=23) and 5 children later evolved to WS/IS. LGS was diagnosed initially in 4 children (1 later revised) and in 22 by the end of follow-up, including 7 evolving from WS/IS and 12 from nonsyndromic generalized, focal or undetermined epilepsies. Evolution to LGS took a median of 1.9 years. LGS developed in 13% of infants, including 9% of those who did not initially present with WS/IS. Significance: DEEs account for disproportionate amounts of pharmacoresistance, disability, and early mortality. LGS often has a window between initial presentation and full expression. LGS, should become targeted for early detection and prevention.

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“…Effective CLN2 disease management requires timely diagnosis; however, irreversible neurodegeneration often occurs before a diagnosis is typically reached at 5 years of age (Nickel et al, ). Early diagnosis has become even more relevant as a recently approved intracerebroventricular enzyme replacement therapy has been shown to effectively slow the rapid decline in motor and language function in patients with CLN2 disease (Schulz et al, ). Aside from genetic testing, there are other medical procedures that may increase suspicion of CLN2 disease, for example, severe cerebellar atrophy is the principal sign seen at the time of diagnosis on magnetic resonance imaging (MRI) (Williams et al, ).…”

Section: Introductionmentioning

confidence: 99%

Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease

et al. 2019

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Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive condition caused by variants in the TPP1 gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase I (TPP1). We update on the spectrum of TPP1 variants associated with CLN2 disease, comprising 131 unique variants from 389 individuals (717 alleles) collected from the literature review, public databases, and laboratory communications. Previously unrecorded individuals were added to the UCL TPP1‐specific database. Two known pathogenic variants, c.509–1 G>C and c.622 C>T (p.(Arg208*)), collectively occur in 60% of affected individuals in the sample, and account for 50% of disease‐associated alleles. At least 86 variants (66%) are private to single families. Homozygosity occurs in 45% of individuals where both alleles are known (87% of reported individuals). Atypical CLN2 disease, TPP1 enzyme deficiency with disease onset and/or progression distinct from classic late‐infantile CLN2, represents 13% of individuals recorded with associated phenotype. NCBI ClinVar currently holds records for 37% of variants collected here. Effective CLN2 disease management requires early diagnosis; however, irreversible neurodegeneration occurs before a diagnosis is typically reached at age 5. Timely classification and public reporting of TPP1 variants is essential as molecular testing increases in use as a first‐line diagnostic test for pediatric‐onset neurological disease.

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Study of Intraventricular Cerliponase Alfa for CLN2 Disease

Cited by 381 publications

References 15 publications

The expanding spectrum of movement disorders in genetic epilepsies

The expanding spectrum of movement disorders in genetic epilepsies

Evolution and course of early life developmental encephalopathic epilepsies: Focus on Lennox‐Gastaut syndrome

Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease

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