Version 5 (October 2012)

NE THAMES REGIONAL MOLECULAR GENETICS SERVICE

Variant Neuronal Ceroid-Lipofuscinosis (CLN5, 6, 7 & 8) Adult Neuronal Ceroid-Lipofuscinosis (CLN6) (variant late-infantile (vLINCL) / adult NCL)

Introduction Contact details Variant type neuronal ceroid-lipofuscinosis (also generally referred to as variant late- infantile Batten’s disease) is a rare autosomal recessive neurodegenerative disorder Molecular Genetics which can be caused by mutations in one of several including CLN5, CLN6, GOSH NHS Trust MFSD8 (CLN7) and CLN8. The CLN6 is also associated with an adult form of Level 6 NCL, Kufs disease. The neuronal ceroid-lipofuscinoses are a group of at least eight York House genetically distinct diseases associated with a similar phenotype but variable age of 37 Queen Square onset. London WC1N 3BH Variant-late infantile NCL (vLINCL) is so called due to the similarity of clinical presentation and age of onset to the classic late-infantile form of NCL. The differential diagnosis of variant NCL from other NCL types is based on age of onset, clinical Telephone phenotype and ultra structural characterisation of the storage material. Characteristic +44 (0) 20 7762 6888 accumulation of auto fluorescent lipopigment with mixed fingerprint/curvilinear/ Fax rectilinear profiles is seen in neurones and other cell types and there is an absence of +44 (0) 20 7813 8196 vacuolated lymphocytes on a blood smear (differentiating this type of NCL from NCL3).

Adult NCL (ANCL) has a similar presentation to the other NCLs but without visual loss

and with a later onset.

The CLN5 gene (13q21.1-q32) consists of 4 exons, CLN6 (15q21-q23) consists of 7 exons, MFSD8 (CLN7) (4q28.2) consists of 13 exons, and CLN8 (8pter-p22) consists of 3 exons. Mutations are generally family specific and found throughout each gene.

Samples required Referrals  Clinical and histopathological review of the affected patient is recommended to

indicate a diagnosis of variant NCL. Please supply details of biochemical and 5ml venous blood in histopathological testing undertaken, clinical details and any relevant plastic EDTA bottles pedigree. If the necessary patient samples are unavailable genetic testing can (>1ml from neonates) be undertaken in the parents of an affected child.

Carrier testing can be offered to the adult relatives of variant NCL patients Prenatals must be  once a disease causing mutation has been identified. arranged in advance, through a Clinical Prenatal testing Genetics department if Prenatal testing is available for families in whom the diagnosis of variant NCL has been possible. Amniotic confirmed by the identification of a mutation or in whom appropriate family studies have fluid or CV samples been undertaken - please contact the laboratory to discuss. should be sent to Cytogenetics for Service offered dissecting and Direct sequencing analysis of all coding exons and intron-exon boundaries of the culturing, with CLN5, CLN6, MFSD8 (CLN7) and CLN8 genes. Genes will be sequenced at the same instructions to forward time, however, a particular gene can be tested on request. the sample to the Adult onset cases will be screened for mutations in the CLN6 gene.

Regional Molecular Genetics laboratory for Target reporting time analysis 8 weeks for routine mutation screening. 2 weeks for routine testing of specific mutations. For urgent samples please contact the laboratory. A completed DNA request card should Contact details for histopathology laboratory: accompany all Histopathology, Level 3, Camelia Botnar Laboratories, Great Ormond Street Hospital, samples. London WC1N 3JH. Tel: +44 (0) 20 7405 9200 (x7907)

Patient details To facilitate accurate testing and reporting please provide patient demographic details (full name, date of birth, address and ethnic origin), details of any relevant family history and full contact details for the referring clinician