Juvenile-onset neuronal ceroid lipofuscinosis with infantile CLN1 mutation and palmitoyl-protein thioesterase deficiency R. Ka ¨ lvia ¨ inen a , K. Eriksson b,c , M. Losekoot d , I. Sorri e , I. Harvima f , P. Santavuori g *, I. Ja ¨ rvela ¨ h , T. Autti i , R. Vanninen j , T. Salmenpera ¨ a and O. P. van Diggelen k a Department of Neurology, Kuopio Epilepsy Center, Kuopio University Hospital and University of Kuopio, Kuopio, Finland; b Pediatric Research Centre, Medical School, University of Tampere, Tampere, Finland; c Pediatric Neurology Unit, Department of Pediatrics, Tampere University Hospital, Tampere, Finland; d Clinical Molecular Genetics Laboratory, Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands; e Department of Ophthalmology, Kuopio University Hospital and University of Kuopio, Kuopio, Finland; f Department of Dermatology, Kuopio University Hospital and University of Kuopio, Kuopio, Finland; g Department of Pediatric Neurology, Hospital for Children and Adolescents, Helsinki University Hospital, Helsinki, Finland; h Laboratory of Molecular Genetics, Helsinki University Hospital, Helsinki, Finland; i Department of Radiology, Helsinki University Hospital, Helsinki, Finland; j Department of Radiology, Kuopio University Hospital and University of Kuopio, Kuopio, Finland; k Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands Keywords: CLN1, juvenile-onset neuronal ceroid lipofusci- nosis, neuronal ceroid lipofuscinosis, palmitoyl protein thioesterase Received 12 April 2006 Accepted 28 September 2006 Accurate diagnosis, especially in progressive hereditary diseases, is essential for the treatment and genetic counseling of the patient and the family. Neuronal ceroid lipofuscinoses (NCL) are amongst the most common groups of neurodegenerative diseases. Infantile, juvenile, and adult-onset types with multiple genotype–phenotype associations have been described. A fluorimetric enzyme assay for palmitoyl protein thioesterase (PPT) from leukocytes and fibroblasts has been previously developed to confirm the diagnosis of infantile NCL. We describe a patient with juvenile-onset NCL phenotype with a new CLN1 mutation and deficient PPT activity. Over 40 different mutations have been found in patients with PPT deficiency, indicating that screening for known mutations is not an efficient way to diagnose this disorder. Therefore, PPT enzyme analysis should precede mutation analysis in suspected PPT deficiency, par- ticularly in patients with granular osmiophilic deposits (GROD) or in patients who have negative ultrastructural data. The use of enzyme assay led to the diagnosis of this patient with juvenile-onset Finnish variant NCL with PPT deficiency, and we expect that greater awareness of the utility of the enzymatic assay may lead to identification of other similar cases awaiting a definitive diagnosis. Introduction Neuronal ceroid lipofuscinoses (NCL) are one of the most common group of neurodegenerative diseases in childhood with autosomal recessive inheritance [1] and global incidence of 1:12 500–21 000 [1,2]. They are characterized by progressive visual failure, progressive dementia and pyramidal or extrapyramidal motor manifestations from cerebellar ataxia to muscular spasticity. They also belong to the group of myoclonic epilepsies [3] presenting with myoclonic, tonic–clonic, and focal seizures. All NCL diseases share intralysosomal accumulation of lipopigments in either granular, curvilinear, or fin- gerprint patterns in various tissues. The main types are infantile-onset Santavuori-Haltia disease (INCL/ CLN1, MIM 256730), late infantile-onset Jansky- Bielschowsky disease (LINCL/CLN2, MIM 204500), juvenile-onset Spielmeyer-Vogt (Batten) disease (JNCL/ CLN3, MIM 204200), and adult-onset KufsÕ disease (ANCL/CLN4, MIM 204300). Variant phenotypes caused by mutations in different CLN genes and over- lapping phenotype-genotype associations exist in dif- ferent forms of NCL diseases [4]. In the infantile-onset INCL a lysosomal enzyme, palmitoyl protein thioesterase (PPT), was found to be deficient in all 42 Finnish INCL patients and one major mutation c.364A>T (Arg122Trp) in the CLN1 (1p32) gene was shown to be present in 98% of affected chromosomes [5]. Since then over 40 other diseases causing mutations have been described in nine exons of the CLN1 gene [6, http://www.ucl.ac.uk/ncl/ Correspondence: Reetta Ka¨lvia¨inen MD, PhD, Kuopio Epilepsy Center, Department of Neurology, Kuopio University Hospital, POB 1777, 70211 Kuopio, Finland (tel.:+358 17 173006; fax: +358 17 173031; e-mail: reetta.kalviainen@kuh.fi). *Deceased Ó 2007 EFNS 369 European Journal of Neurology 2007, 14: 369–372 doi:10.1111/j.1468-1331.2006.01668.x