Neuronal ceroid-lipofuscinosis type 2 (NCL2; MIM #204500) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the TPP1 gene which encodes the lysosomal enzyme tripeptidyl peptidase. NCL2 is one of at least eight genetically distinct diseases associated with the NCL disease spectrum. NCL2 is generally referred to as late-infantile NCL (LINCL) due typical onset of symptoms between the ages of 2 and 4 years. Variant forms of LINCL (vLINCL) have been reported to be caused by mutations in the CLN1, CLN5, CLN6, CLN7 and CLN8 genes. Clinical features of LINCL are normal development until the onset of seizures, ataxia and myoclonus between 2 and 4 yrs. LINCL usually progresses with visual loss (by 5-6 yrs), chair bound by 4-6 yrs with poor prognosis. The differential diagnosis of NCL2 from the other NCL types is based on age of onset, clinical phenotype, ultra structural characterisation of the storage material and TPP1 enzyme levels. A clinical diagnosis of NCL2 is confirmed biochemically by loss of tripeptidylpeptidase I (TPP1) enzyme activity in leucocytes and fibroblasts or accumulation of auto fluorescent lipopigment with a curvilinear profile in neurones and other cell types.
Also known as
Late infantile Batten disease; Jansky-Bielschowski disease, CLN2
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Clinically affected patients should, wherever possible, have their diagnosis confirmed by analysis of TPP1 enzyme activity in leucocytes and fibroblasts. This should be arranged locally or with the Enzyme Unit, Great Ormond Street Hospital. Biochemically confirmed patients can be referred for mutation analysis. If the necessary patient samples are unavailable genetic testing can be undertaken in the parents of an affected child. TPP1 (11p15) consists of 13 exons. The two most common mutations are c.509-1G>C (~33% of LINCL chromosomes) and p.Arg208X (~26 % of LINCL chromosomes). Other disease causing mutations are family specific and found throughout the gene. Level 1 Mutation Analysis: Detection of recurrent mutations c.509-1G>C and p.Arg208X in exon 6 by direct sequencing analysis. Level 2 Mutation Analysis: Direct sequencing of all 13 coding exons and intron-exon boundaries.
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Great Ormond Street Hospital NE Thames Regional Genetics Service Laboratories
Great Ormond Street Hospital for Children
37 Queen Square
1ml EDTA neonates, 5ml EDTA adults
Common mutations - 20 days; gene screen - 40 days
Disease / group
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Prenatals must be arranged in advance, through a Clinical Genetics department if possible. Amniotic fluid or CV samples should be sent to Cytogenetics for dissecting and culturing, with instructions to forward the sample to the Regional Molecular Genetics laboratory for analysis