Neuronal Ceroid Lipofuscinoses Workup

  • Author: Celia H Chang, MD; Chief Editor: Amy Kao, MD   more...
 
Updated: Sep 17, 2009
 

Laboratory Studies

  • Enzyme levels
    • CLN1: Palmitoyl protein thioesterase (PPT) levels can be measured in leukocytes, cultured fibroblasts, dried blood spots, and saliva. Lymphoblast PPT < 0.2 pmoles/min/mg (normal levels 1-3).
    • CLN2: Tripeptidyl peptidase 1 (TTP1) levels can be measured in leukocytes, cultured fibroblasts, dried blood spots, and saliva. Fibroblast TTP1 activity is approximately 17,000 micromoles of amino acids produced per hour per mg of protein. The TTP1 activity in CLN2 is less than 4% of normal.
  • Other biochemical abnormalities include accumulation of subunit C of the ATP synthase complex (SCMAS) in lysosomes of patients with NCLs caused by mutations in CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, or CLN8. In CLN3, a large proportion of lymphocytes contain cytoplasmic vacuoles.
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Imaging Studies

  • MRI
    • CLN1
      • Mild cerebral atrophy progresses after 4
      • Decreased T2-signal intensity in the thalami
      • Callosal thinning
      • Periventricular rims of hyperintensity that progress to diffuse white matter hyperintensity on T2
      • Cerebellar atrophy after age 3 years
    • CLN2 - Progressive atrophy, especially infratentorial
      • Dyke et al found that a whole brain apparent diffusion coefficient (ADC) correlated with the patient's age and disease duration. They found that the children with CLN2 began to differ from controls at age 5.[5]
    • CLN3
      • Cerebral atrophy
      • Cerebellar atrophy usually after age 15 years
      • Voxel-based morphometric study[6]
        • Marked reduction in the gray matter volume of the dorsomedial thalami in particular
        • Decreased white matter volume of the corona radiata
    • CLN6 - Severe cerebral and cerebellar atrophy
  • Positron emission tomography
    • CLN2 - Severe generalized hypometabolism
    • CLN3 - Hypometabolism, earliest in the calcarine area
  • Magnetic resonance spectroscopy
    • CLN1
      • Almost complete loss of N- acetylaspartate (metabolite present only in neurons)
      • Reduction in creatine- and choline-containing compounds (ie, markers for glial membrane turnover)
      • Elevation of myoinositol (ie, a glial marker)
      • Elevation of lactate in both gray and white matter
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Other Tests

  • EEG
    • CLN1 (Infantile form)
      • Lack of attenuation of posterior dominant rhythm to eye opening
      • Loss of sleep spindles
      • Progressive background abnormality and attenuation with the background flat by age 3 years
    • CLN2 - Occipital spikes with photic stimulation at 1-2 Hz
    • CLN3
      • Disorganized
      • Spike and slow wave complexes
  • Electroretinogram (ERG)
    • CLN1 (Infantile form) - Unrecordable at age 3 years
    • CLN1 (Juvenile form) - Unrecordable at diagnosis
    • CLN2 (Late infantile form) - Abnormal at presentation and then extinguishes
    • CLN3 - Abnormal early
  • Visual-evoked potential
    • CLN1 (Infantile form) - Unrecordable at age 4 years
    • CLN2 (Late infantile form) - Abnormally enhanced but diminish in final stages
    • CLN3 - Abnormal early
  • Somatosensory evoked potential (SSEP) - Progressive attenuation in all NCLs
  • Neuropsychological testing: Adams et al found that children with CLN3 had significant impairment in auditory attention, memory, verbal intellectual function, and fluency. Neuropsychological impairment was progressive over time and correlated with disease duration and motor function.[7]
  • DNA testing and electron microscopic ultrastructural findings in peripheral blood lymphocytes[8] may be used, as well as other tissues. Resources such as genetests.org can be used to determine updated availability of genetic testing on clinical or research basis.
    • INCL -CLN1 gene localizes to chromosome 1p32
    • [Granular osmiophilic deposits = GROD]
    • LINCL -CLN2 gene localizes to chromosome 11p15.5 [Curvilinear bodies = CV/Mixed]
    • JNCL -CLN3 gene localizes to chromosome 16p12.1 [Fingerprint profiles = FP/mixed]
    • ANCL -CLN4 gene not mapped yet [FP/granular]
    • fLINCL -CLN5 gene localizes to chromosome 13q21.1-q32 [FP, CV, rectilinear complex = RL]
    • pLINCL -CLN6 gene localizes to chromosome 15q21-q23 [CV, FP, RL]
    • tLINCL -CLN7 gene mapped to 4q28.1-q28.2 [FP/mixed]
    • PEMR -CLN8 gene localizes to chromosome 8p23
    • [CV or GROD-like inclusions]
    • CLN9 [GROD, CV, FP]
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Histologic Findings

Histologic findings include the following:

  • CLN1 - Almost complete loss of cortical neurons
  • CLN3
    • Vacuolated lymphocytes
    • Selective necrosis of stellate cells in layers 2 and 3 and loss of pyramidal cells in layer 5
  • CLN5
    • Neuronal loss in the neocortex and cerebellum
    • Laminar pattern of neuronal loss, most severe layers III and V
    • Meganeurities in layer III
    • Extensive gliosis
    • Almost complete loss of Purkinje and granule cells with gliosis
  • CLN6
    • Neuronal loss, especially layer V
    • Loss of granule cells with relative preservation of Purkinje cells
    • SCMAS absent in liver, adrenals, and pancreas
  • CLN8
    • Slight loss in layer V and CA2 in hippocampus
    • SCMAS most prominent in layer III and hippocampus CA2-CA4
    • Meganeurites in layer III
    • Minimal SCMAS in Purkinje cells, substantia nigra, and locus ceruleus
    • Unlike other lysosomal storage diseases, usually no ectopic dendritic growth or axonal spheroids
    • Meganeurites caused by distention of the axon hillock and proximal axon (occasionally)
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Staging

CLN2: Worgall et al found that the Weill Cornell LINCL scale correlated better than the modified Hamburg LINCL scale with age and time since onset of initial clinical manifestations. They also found that imaging measures also correlated better with the Weill Cornell scale.[9]

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Contributor Information and Disclosures
Author

Celia H Chang, MD  Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis

Celia H Chang, MD is a member of the following medical societies: American Academy of Neurology and Child Neurology Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Beth A Pletcher, MD  Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey

Beth A Pletcher, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Kenneth J Mack, MD, PhD  Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic

Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience

Disclosure: Nothing to disclose.

,  Kathy Roarty Placeholder

Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD  Assistant Professor, Department of Pediatrics, Division of Pediatric Neurology, Department of Neurology, Oregon Health and Science University; Consulting Staff, Shriners Hospital for Children

Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society

Disclosure: Nothing to disclose.

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