GTR Home > Tests > Neuronal Ceroid-Lipofuscinoses Panel

Overview

Test name

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Neuronal Ceroid-Lipofuscinoses Panel

Purpose of the test

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This is a clinical test intended for Help: Risk Assessment, Monitoring, Diagnosis, Mutation Confirmation, Screening, Pre-symptomatic

Condition

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8 conditions tested. Click Indication tab for more information.

Methodology

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Molecular Genetics
DDeletion/duplication analysis
Microarray
CSequence analysis of the entire coding region
Next-Generation (NGS)/Massively parallel sequencing (MPS)

Summary of what is tested

8 genes and variants. Click Methodology tab for more information.

Genes

Clinical validity

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Mutations in CLN3 are the main cause of classic juvenile NCL. The first symptom is typically insidious onset of retinitis pigmentosa at age 4-6 years, followed by progressive cognitive decline and seizures. Other symptoms may include myoclonus, parkinsonism, severe dysarthria and behavioral issues with angry outbursts and physical violence. CLN3 mutations may also be associated with adult NCL in some cases. The CLN3 protein localizes to the lysosomes, and has been hypothesized to play a role in regulating neuronal cell death. Mutations in CLN5 are associated with the Finnish variant of late infantile NCL. The disorder was first identified in 18 Finnish families of common ancestry, with features including intellectual disability, ataxia and myoclonic epilepsy. Age of onset is typically around age 4-7 years. Mutations in CLN5 have since been described outside of the Finnish population. CLN5 mutations may also be associated with adult NCL in some cases. CLN5 is a lysosomal protein, and mutations in this gene are associated with defective lysosomal trafficking. CLN6 mutations are associated with the “Early Juvenile” variant of late infantile NCL. Age of onset is typically around between 1-8 years, and presenting symptoms typically include vision loss and seizures. For children with age of onset after 4 years, epilepsy, ataxia and myoclonus may be the presenting features. Studies of CLN6 mouse models revealed changes in the expression levels of proteins involved in synaptic function and stability and cell-cycle regulation. Mutations in the CLN8 gene can be associated with either the “Northern Epilepsy” variant of NCL (NE), or late infantile NCL. The NE phenotype is characterized by tonic-clonic or complex-partial seizures, intellectual decline and motor dysfunction. There is a specific mutation in CLN8 which is associated with the NE phenotype, which has a founder effect in the Finnish population. CLN8 is a transmembrane protein in the endoplasmic reticulum, and functional studies have found that neuronal cellular proliferation is increased in cell lines with CLN8 mutations. CTSD mutations have been identified in patients with congenital NCL, which is the most severe NCL subtype. Findings include microcephaly, seizures, extensive neural loss, gliosis and early death. CTSD mutations may also be observed in other subtypes of NCL, including late infantile, juvenile and adult. CTSD encodes for a lysosomal proteinase involved in proteolytic degradation, cell invasion and apoptosis. It has been hypothesized that patients who retain some residual enzyme activity have a less severe phenotype and a later age of onset than those with complete loss of activity. Mutations in MFSD8 are associated with a variant of late infantile NCL. Mutations were first identified in Turkish patients who presented with seizures and/or motor impairment at an average age of 5 years. The patients later developed developmental regression, myoclonus, speech impairment, vision loss and personality disorders. The MFSD8 protein localizes to the lysosome and functions as a transporter protein, however further details regarding the function of the MFSD8 protein are yet to be elucidated. PPT1 mutations have been described in association with several different subtypes of NCL, including infantile, late infantile, juvenile and adult. PPT1 encodes a lysosomal enzyme with “housekeeping” role, it has also been hypothesized to play a role in synaptic functioning. Mutations in TPP1 are typically associated with classic late infantile NCL, and age of onset is typically around 2-4 years. Presenting symptoms are usually seizures, cognitive decline and vision loss. TPP1 is also a rare cause of JNCL. TPP1 encodes for a serine-carboxyl peptidase that localizes to the lysosome.

Citations
  • Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder. - PubMed ID: 10330339
  • Palmitoyl protein thioesterase (PPT) localizes into synaptosomes and synaptic vesicles in neurons: implications for infantile neuronal ceroid lipofuscinosis (INCL). - PubMed ID: 11136716
  • Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein. - PubMed ID: 11971870
  • Neurology of the neuronal ceroid-lipofuscinoses: late infantile and juvenile types. - PubMed ID: 1609833
  • The spectrum of Jansky-Bielschowsky disease. - PubMed ID: 1649978
  • Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin. - PubMed ID: 17189291
  • The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. - PubMed ID: 17564970
  • Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10). - PubMed ID: 18762956
  • A novel CLN8 mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function. - PubMed ID: 19431184
  • Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease. - PubMed ID: 19640925
  • Mole, S., Neuronal Ceroid-Lipofuscinoses. 2001 Oct 10 [Updated 2010 Mar 2], GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.

Clinical utility

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Establish or confirm diagnosis

Citations
  • Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder. - PubMed ID: 10330339
  • Palmitoyl protein thioesterase (PPT) localizes into synaptosomes and synaptic vesicles in neurons: implications for infantile neuronal ceroid lipofuscinosis (INCL). - PubMed ID: 11136716
  • Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein. - PubMed ID: 11971870
  • Neurology of the neuronal ceroid-lipofuscinoses: late infantile and juvenile types. - PubMed ID: 1609833
  • The spectrum of Jansky-Bielschowsky disease. - PubMed ID: 1649978
  • Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin. - PubMed ID: 17189291
  • The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. - PubMed ID: 17564970
  • Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10). - PubMed ID: 18762956
  • A novel CLN8 mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function. - PubMed ID: 19431184
  • Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease. - PubMed ID: 19640925

How to order

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All samples should be shipped via overnight delivery at room temperature. No weekend or holiday deliveries. Label each specimen with the patient’s name, date of birth and date sample collected. Send specimens with complete requisition and consent form, otherwise, specimen processing may be delayed.
Order URL Help: http://dnatesting.uchicago.edu/submitting-sample

Test services

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  • Clinical Testing/Confirmation of Mutations Identified Previously
  • Confirmation of research findings
  • Custom Prenatal Testing
  • Custom mutation-specific/Carrier testing

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