CLN3 disease: Casuistry of the Córdoba, Argentina cohort within the framework of world evidence on Neuraonal Ceroid Lipofuscinoses (NCL)

Abstract

Abstract: 

CLN3 disease (OMIM # 204200), Juvenile Ceroid Lipofuscinosis (CLN) or Batten's Disease, is the most common form of NCL in the Northern Hemisphere. Its prevalence in Latin America is unknown. It is caused by pathogenic variants in the CLN3 gene located on chromosome 16. The gene encodes a transmembrane protein involved in lysosomal homeostasis. Although the retinal phenotype is relatively uniform throughout the spectrum of the disease, the grade of pathogenicity of the pathological variants in the CLN3 gene determines the neurocognitive and motor consequences. Vacuolated lymphocytes in a child with retinal dystrophy is pathognomonic for CLN3 (classic). The present work is a retrospective observational study of the CLN3 casuistry in the Córdoba cohort in the context of published evidence to offer an analytical framework for phenotypic, proteomic and genomic characterization in Latin America. The children were studied under the algorithm developed at the Hospital de Niños de Córdoba. 1.Clinical compatibility was evaluated. 2. A May-Grunwald-Giemsa stained blood smear was analyzed for at least 3% vacuolated lymphocytes under light microscopy. 3. A skin and / or muscle biopsy was studied under electron microscopy for the detection of characteristic osmophilic bodies. 4. Genotypes were studied by PCR followed by Sanger sequencing. 5. We searched for the evidence published in the period 2011-2021 under the keywords CLN3, juvenile CLN, Batten's disease, casuistry. Latin American literature was searched on the Scielo portal. The Córdoba cohort of CLN3 disease consists of 6 individuals with the classic CLN3 phenotype. It is the second most common form of NCL after CLN2. The 6/6 individuals presented the most common deletion of 1.02 kb; 3/6 in homozygous and the other 3/6 in compound heterozygous combination with another DNA variant. In the world experience more than 90% of all cases showed the most common deletion 1.02kb (c.462_677 del) in homozygosis. This fact could be due to the high grade of mixed ethnicities in Latin America. Cohort studies of CLN3 in Latin America are very scarce, and this type of NCL is possibly underdiagnosed.