Approach Considerations
Biochemical abnormalities in neuronal ceroid lipofuscinoses (NCLs) include the accumulation of subunit C of the ATP synthase complex (SCMAS) in the lysosomes of patients with mutations in CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, or CLN8. In CLN3 NCL, a large proportion of lymphocytes contain cytoplasmic vacuoles.
Enzyme levels
CLN1 NCL
Palmitoyl protein thioesterase (PPT) levels can be measured in leukocytes, cultured fibroblasts, dried blood spots, and saliva. Lymphoblast PPT is less than 0.2pmoles/min/mg (normal levels are 1-3). [19]
CLN2 NCL
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 NCL is less than 4% of normal. [19, 20]
Electroencephalography
Electroencephalographic characteristics seen in CLN1 NCL (infantile form) include the following:
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Lack of attenuation of posterior dominant rhythm to eye opening
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Loss of sleep spindles
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Progressive background abnormality and attenuation with the background flat by age 3 years
In CLN2 NCL, occipital spikes with photic stimulation at 1-2 Hz are seen on electroencephalograms (EEGs). In CLN3 NCL, the results are disorganized, and spike and slow wave complexes are seen.
Electroretinography
On electroretinography, characteristics include the following:
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CLN1 NCL (infantile form) - Unrecordable at age 3 years
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CLN1 NCL (juvenile form) - Unrecordable at diagnosis
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CLN2 NCL (late-infantile form) - Abnormal at presentation and then extinguishes
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CLN3 NCL - Abnormal early
Visual evoked potential
Visual evoked-potential studies are characterized as follows:
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CLN1 NCL (infantile form) - Unrecordable at age 4 years
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CLN2 NCL (late-infantile form) - Abnormally enhanced, but diminish in the final stages
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CLN3 NCL - Abnormal early
Somatosensory evoked potential
Progressive attenuation in all NCLs is seen in somatosensory evoked-potential studies.
Staging
In CLN2 NCL, Worgall et al found that the Weill Cornell late-infantile NCL (LINCL) scale correlated better than the modified Hamburg LINCL scale did with age and time since the onset of initial clinical manifestations. In addition, they found that imaging measures also correlated better with the Weill Cornell scale. [21]
MRI and MR Spectroscopy
CLN1 NCL
Magnetic resonance imaging (MRI) findings in CLN1 NCL include the following:
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Mild cerebral atrophy progresses after 4
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Decreased T2-signal intensity in the thalami
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Callosal thinning
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Periventricular rims of hyperintensity that progress to diffuse white matter hyperintensity on T2
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Cerebellar atrophy after age 3 years
In magnetic resonance (MR) spectroscopy, the following characteristics are seen in CLN1 NCL:
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Almost complete loss of N- acetylaspartate (metabolite present only in neurons)
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Reduction in creatine- and choline-containing compounds (ie, markers for glial membrane turnover)
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Elevation of myoinositol (ie, a glial marker)
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Elevation of lactate in gray and white matter
CLN2 NCL
In CLN2 NCL, progressive atrophy, especially infratentorial atrophy, is seen. In a study, Dyke et al found that a whole-brain apparent diffusion coefficient (ADC) correlated with the patient's age and disease duration. They determined that children in the study with CLN2 began to differ from controls at age 5 years. [22]
CLN3 NCL
MRI findings in CLN3 NCL include the following:
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Cerebral atrophy
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Cerebellar atrophy usually after age 15 years
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In voxel-based morphometric study [23] - Marked reduction in the gray matter volume of the dorsomedial thalami in particular and decreased white matter volume of the corona radiata are seen
CLN6 NCL
MRI findings in CLN6 NCL include severe cerebral and cerebellar atrophy.
PET Scanning
In positron emission tomography (PET) scanning, the following characteristics are seen:
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CLN2 NCL - Severe, generalized hypometabolism
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CLN3 NCL - Hypometabolism, earliest in the calcarine area
DNA Testing
DNA testing and electron microscopic ultrastructural findings in peripheral blood lymphocytes [24] may be used, as well as other tissues. Resources such as genetests.org can be used to determine updated availability of genetic testing on a clinical or research basis. DNA testing considerations regarding CLN genes include the following:
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Infantile NCL (INCL) -CLN1 gene localizes to chromosome 1p32 [Granular osmiophilic deposits = GROD]
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Late-infantile NCL (LINCL) -CLN2 gene localizes to chromosome 11p15.5 [Curvilinear bodies = CV/Mixed]
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Juvenile NCL (JNCL) -CLN3 gene localizes to chromosome 16p12.1 [Fingerprint profiles = FP/mixed]
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Adult NCL (ANCL) -CLN4 gene not mapped yet [FP/granular]
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Finnish variant late-infantile NCL (fLINCL) -CLN5 gene localizes to chromosome 13q21.1-q32 [FP, CV, rectilinear complex = RL]
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Portuguese variant late-infantile NCL (pLINCL) -CLN6 gene localizes to chromosome 15q21-q23 [CV, FP, RL]
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Turkish variant late-infantile NCL (tLINCL) -CLN7 gene mapped to 4q28.1-q28.2 [FP/mixed]
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Progressive epilepsy with mental retardation (PEMR) -CLN8 gene localizes to chromosome 8p23 [CV or GROD-like inclusions]
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CLN9 [GROD, CV, FP]
Histology
Histologic findings in CLN1 NCL include an almost complete loss of cortical neurons. In CLN3 NCL, findings include vacuolated lymphocytes, as well as selective necrosis of stellate cells in layers II and III and loss of pyramidal cells in layer V.
Findings in CLN5 NCL include the following:
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Neuronal loss in the neocortex and cerebellum
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Laminar pattern of neuronal loss, most severe in layers III and V
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Meganeurites in layer III
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Extensive gliosis
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Almost complete loss of Purkinje and granule cells with gliosis
Findings in CLN6 NCL include the following:
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Neuronal loss, especially layer V
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Loss of granule cells, with relative preservation of Purkinje cells
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SCMAS absent in liver, adrenals, and pancreas
Findings in CLN8 NCL include the following:
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Slight loss in layer V and CA2 in hippocampus
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SCMAS most prominent in layer III and hippocampus CA2-CA4
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Meganeurites in layer III
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Minimal SCMAS in Purkinje cells, substantia nigra, and locus ceruleus
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Unlike other lysosomal storage diseases, usually no ectopic dendritic growth or axonal spheroids
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Meganeurites caused by distention of the axon hillock and proximal axon (occasionally)
