The Neuronal Ceroid Lipofuscinoses (NCL) is probably the most frequent group of progressive inherited neurodegenerative diseases with childhood onset. They can start at all ages and progression is characterized by one or more of the following symptoms: vision failure, seizures, mental and motor regression. The outcome is fatal with therapies being symptomatic and palliative. We present preliminary data indicating that NCLs are under diagnosed in South America. We will collaborate with the Batten Disease Diagnostic and Clinical Research Center (BDDCRC) at the University of Rochester. The initial aim of this application is to establish and improve upon existing technologies for diagnosis of NCLs in South America. In addition, through our collaboration we will also refine our understanding of the clinical characteristics, progression and genotype to phenotype correlations for NCLs in South America. Finally, we will establish the basis for identifying secondary Biomarkers for monitoring clinical status for improved monitoring of disease progression for application of treatment strategies. We propose the following specific aims: 1.) Development of NCL Diagnostic Tools. 2.) Genotype to Phenotype Correlation for South American NCLs. 3.) Development of Biomarkers for NCLs. Recent advances have greatly expanded knowledge of genetics and biology of the NCLs. These advances have provided the basis for experimental therapeutics in NCL. The need for development of new therapeutic interventions is great;current treatment is limited to symptom management when possible, with a shift to palliative care for end-stage disease. Before new interventions can be evaluated rigorously, quantitative natural history data must be obtained and a valid, reliable outcome measure must be developed.
The present translational investigation will overcome under diagnosis of NCLs South America. Affected patients and their families will benefit from diagnosis and prognosis and appropriate care can be followed. Moreover, the unique population will allow for detailed research applicable to the NCL families at risk in S. America and development of a greater global understanding of the genetic and biochemical diversity evidenced in the NCLs.
|Kovács, Attila D; Hof, Caitlin; Pearce, David A (2015) Abnormally increased surface expression of AMPA receptors in the cerebellum, cortex and striatum of Cln3(-/-) mice. Neurosci Lett 607:29-34|
|Kovács, Attila D; Pearce, David A (2015) Finding the most appropriate mouse model of juvenile CLN3 (Batten) disease for therapeutic studies: the importance of genetic background and gender. Dis Model Mech 8:351-61|
|Kohan, Romina; Carabelos, Maria Noelia; Xin, Winnie et al. (2013) Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America. Gene 516:114-21|
|Kovacs, Attila D; Saje, Angelika; Wong, Andrew et al. (2011) Temporary inhibition of AMPA receptors induces a prolonged improvement of motor performance in a mouse model of juvenile Batten disease. Neuropharmacology 60:405-9|
|Kohan, R; Cismondi, I A; Oller-Ramirez, A M et al. (2011) Therapeutic approaches to the challenge of neuronal ceroid lipofuscinoses. Curr Pharm Biotechnol 12:867-83|
|Finn, Rozzy; Kovacs, Attila D; Pearce, David A (2011) Altered sensitivity of cerebellar granule cells to glutamate receptor overactivation in the Cln3(ýýex7/8)-knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. Neurochem Int 58:648-55|