SickKids

Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
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Neuronal Ceroid Lipofuscinoses (NCLs, Batten Disease)

Background
Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
For More Information

Background

Neuronal Ceroid Lipofuscinoses (NCLs, Batten disease) are the most common neurodegenerative disorders of childhood, with an incidence of about 1 in 25,000 births. Several subtypes of the disease are classified on the basis of age of onset, clinical features, biochemical analysis and detailed pathological examination of patient tissue with electron microscopy.

Recent research has identified eight genes which can result in NCL. Six of these have been cloned, and several recurrent mutations accounting for ~80% of the disease in patients have been identified. In addition more than 100 rare CLN gene mutations causing NCL have been detected. There is significant ethnic variation in the frequency of the recurrent mutations.

The disease is present when a child receives two copies of a defective gene, one from each parent. Any person with one copy of the defective CLN gene is a Batten carrier. Carriers do not have, and will never develop, Batten disease. However, if two carriers wish to have children, there is a one in four chance (25%) that their baby will be born with Batten disease. There is a three in four chance (75%) that their baby will not have Batten disease.

Who should be tested

  • individuals clinically or biochemically suspected of being affected with Batten disease
  • individuals with a family history of Batten disease, where the CLN mutations have been identified in the proband, to determine the carrier status of unaffected individuals
  • pregnancies at risk due to a family history of Batten disease

Testing Methodology

This assay consists of two stages:

  1. A direct mutation detection assay is used to test proband samples for five recurrent mutations in CLN1, CLN2 and CLN3

Gene

Mutation

CLN1

c.451C>T (p.Arg151X)

 

c.223A>C (p.Thr75Pro)

CLN2

c.622C>T (p.Arg208X)

 

c.851G>T (p.Gly284Val)

CLN3

1.02Kb del

  1. Direct sequence analysis is used to detect other rare single base changes in the CLN genes.

Detailed clinical, biochemical and pathology information on the patient will be used to prioritize the CLN gene sequencing order in order to maximize the efficiency of analysis .

Potential Outcomes & Interpretation of Test Results

Reason for referral

CLN Gene Mutations
allele 1 / allele 2

Explanation

carrier testing

none detected / none detected

  • This individual is unlikely to be a carrier of Batten disease.

carrier testing

mutation detected / none detected

  • This individual is a carrier of Batten disease, and may transmit a mutation to offspring.

diagnosis

none detected / none detected

  • This result does not support a diagnosis of Batten disease.

diagnosis

mutation detected / none detected

  • This result is unable to confirm a diagnosis of Batten disease.

diagnosis

mutation detected / mutation detected

  • This result confirms a diagnosis of Batten disease.

Cautions:

  • Current molecular testing will not detect all possible mutations in this gene. A negative result does not rule out the possibility that the individual carries a rare CLN mutation not included in the assay.
  • Test results should be interpreted in the context of clinical findings, family history, ethnic background and other laboratory data.
  • This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

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