Molecular diagnosis of and carrier screening for the neuronal ceroid lipofuscinoses

The neuronal ceroid lipofuscinoses (NCLs) are a large group of autosomal re cessive lysosomal storage disorders with both enzymatic deficiency and stru ctural protein dysfunction, Three typical forms, the infantile (INCL), late -infantile (LINCL), and juvenile (JNCL), are among the most common childhoo d-onset neurodegenerative disorders. They result from mutations on genes CL N1, 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 dele tion of a 1.02-kb genomic fragment in CLN3 are the five common mutations fo r NCL, To offer clinical genetic testing for the NCLs, we have developed si mple and quick PCR-based molecular tests for detecting INCL-, LINCL-, and J NCL-affected individuals from 180 NCL families (27 INCL, 76 LINCL, and 77 J NCL), The sensitivity of testing to detect NCL patients among clinically su spected 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 iden tified 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 add ition, 5% (9/180) of NCL patients revealed genetic heterogeneity and were r eclassified. Seven patients previously diagnosed as having JNCL were now fo und to carry mutations of CLN2 (5/7) or CLN1 (2/7) and 2 with late-infantil e onsets were identified as carrying mutations of CLN1. Our data demonstrat e the importance of DNA testing to detect accurately both affected individu als and carriers in NCL families.