Molecular Diagnosis of and Carrier Screening for the Neuronal Ceroid Lipofuscinoses

Abstract

The neuronal ceroid lipofuscinoses (NCLs) are a large group of autosomal recessive lysosomal storage disorders with both enzymatic deficiency and structural protein dysfunction. Three typical forms, the infantile (INCL), late-infantile (LINCL), and juvenile (JNCL), are among the most common childhood-onset neurodegenerative disorders. They result from mutations on genes CLN₁, CLN₂, and CLN₃, respectively. We determined that the mutations 223A → G and 451C → T in CLN₁, T523-1G → C, and 636 C → T in CLN₂, and deletion of a 1.02-kb genomic fragment in CLN₃ are the five common mutations for NCL. To offer clinical genetic testing for the NCLs, we have developed simple and quick PCR-based molecular tests for detecting INCL-, LINCL-, and JNCL-affected individuals from 180 NCL families (27 INCL, 76 LINCL, and 77 JNCL). The sensitivity of testing to detect NCL patients among clinically suspected individuals was determined to be 78% (21/27) for INCL, 66% (54/76) for LINCL, and 75% (58/77) for JNCL. When molecular screening for carriers was conducted among the normal siblings or parents of the probands, we identified two carriers out of three individuals tested for INCL, 20/56 (35.7%) carriers for LINCL, and 48/106 (45.3%) carriers for JNCL families. In addition, 5% (9/180) of NCL patients revealed genetic heterogeneity and were reclassified. Seven patients previously diagnosed as having JNCL were now found to carry mutations of CLN₂ (5/7) or CLN₁ (2/7) and 2 with late-infantile onsets were identified as carrying mutations of CLN₁. Our data demonstrate the importance of DNA testing to detect accurately both affected individuals and carriers in NCL families.