ELSEVIER Studies of Atypical JNCL Suggest Overlapping With Other NCL Forms Krystyna E. Wisniewski, MD, PhD *‘, Nan Zhong, MD’, Wojciech Kaczmarski, PhD*, Aleksandra Kaczmarski, MD*, Susan Sklower-Brooks, MD’, and William T. Brown, MD, PhDt” In the United States, juvenile neuronal ceroid-lipofus- cinosis (JNCL) is the most common form of NCL. This study analyzed 191 cases, diagnosed on the basis of age-at-onset, clinical symptomatology, and pathologic findings. Twenty percent (40/191) of these cases from 24/120 families manifested atypical clinical symptom- atology and/or pathologic findings (typical revealed fingerprints and atypical revealed mixed inclusions, or only curvilinear or granular profiles) and, therefore, represent variant forms of JNCL. Those patients in the study with typical JNCL were a uniform group of cases, whereas the atypical were heterogenous and were divided into 8 subgroups based on the clinico- pathologic findings. Forty-three families were analyzed (27 typical, 16 atypical) for the common 1.02 kb deletion and several pedigrees for novel mutations. In typical JNCL the common 1.02 kb deletion in both alleles (homozygous) were observed in 23/27, and only 1 allele (heterozygous) was exhibited in 4/27 families. In atypical JNCL families, 5/16 were heterozygous for the common 1.02 kb deletion. None of the remaining 11/16 families had the common 1.02 kb deletion in either allele, but in 9/11 cases the palmitoyl-protein thioesterase (PPT) levels were deficient. In cases where the mutation in CLN3 gene has not been identified, several possibilities may exist. The phenotype may be caused by a yet undefined mutation in CLN3 or may be due to overlapping with other forms of NCL. 0 1998 by Elsevier Science Inc. All rights reserved. Wisniewski KE, Zhong N, Kaczmarski W, Kaczmarski A, Sklower-Brooks S, Brown WT. Studies of atypical JNCL suggest overlapping with other NCL forms. Pediatr Neurol 1998;18:36-40. Introduction The neuronal ceroid-lipofuscinoses (NCLs) of child- hood are a group of progressive neurogenetic diseases with an autosomal-recessive mode of inheritance. In rare instances, adults are affected with a dominantly inherited NCL. The consistent finding in all NCLs is autofluores- cent lipopigment storage at the light microscopic level, and fingerprints, curvilinear, granular, or mixed profiles in the lysosomal storage material at the ultrastructural (EM) level [ 1,2]. The NCLs are classified into 4 major forms on the basis of age-at-onset, clinical presentation, morpho- logic findings, and genetic loci: type 1, infantile (INCL, CLNl) Santavuori-Haltia disease caused by the defects in the palmitoyl-protein thioesterase gene (PPT) localized on chromosome 1~32 [3]; type 2, late infantile (LINCL, CLN2) Jansky-Bielschowsky disease, mapped to chromo- some 11~15 [4-61; type 3, juvenile NCL (JNCL, CLN3), Batten disease [7] mapped to chromosome 16~12.1 and commonly caused by a 1.02 kb genomic deletion (81% of chromosomes) [8]; and type 4, adult NCL (ANCL, CLN4) Kufs disease [9], in which assignment of the gene to chromosomal region has not been achieved. JNCL is the most common form of NCL in the United States. Atypical forms that do not fit the 4 classic types of NCL, which have been described previously [1,2,10], occur in 20% of NCL cases. Recent progress in the biochemistry and molecular genetics of NCL led to this reevaluation of atypical JNCL cases. Material and Methods A total of 191 JNCL cases have been reviewed to identify patients that had atypical clinical, pathologic, biochemical, or genetic presentation. The definition of typical and atypical JNCL cases was published previously [ 1,2, lo]. Special attention was given to differing age-at-onset, From the Departments of *Pathological Neurobiology and +Human Genetics; New York State Institute for Basic Research in Developmental Disabilities; Staten Island; and *State University of New York/Health Science Center at Brooklyn; Brooklyn, New York. Communications should be addressed to: Dr. Wisniewski; Department of Pathological Neurobiology; NYS Institute for Basic Research; 1050 Forest Hill Road, Staten Island, NY 10314. Received April 16, 1997; accepted June 27, 1997. 36 PEDIATRIC NEUROLOGY Vol. 18 No. 1 0 1998 by Elsevier Science Inc. All rights reserved. PI1 SO887-8994(97100188-4 . 0887-8994/9X/219 00