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1.6.5 NEURONAL CEROID LIPOFUSCINOSES

NCL consists of a group of genetically determined neurodegenerative disorders characterized by the accumulation of abnormal amounts of fluorescent lipopigments, which include lipofuscin and ceroid, within neuronal perikarya142;143.

The disorder was initially classified as a form of amaurotic familial idiocy due to the presence of visual loss and dementia.  The histological accompaniment of amaurotic  familial idiocy was widespread distention of neurons by lipid material.  With time, infantile amaurotic familial idiocy (Tay-Sachs disease) was separated from late infantile/juvenile amaurotic familial idiocy (NCL).  The adult variant of NCL was recognized in 1925.

 

There are four clinical and genetic subtypes 144

1. The infantile type does not present as a PME syndrome48.

2. The late infantile form (Janský-Bielschowsky disease) is an AR disorder that starts between the ages of 2 and 4 years with a wide range of seizure types including atypical absence, atonic and tonic-clonic seizures69.  Shortly after the onset of seizures, ataxia, dementia and stimulus-sensitive myoclonic seizures develop, with myoclonus being a prominent feature, including “myoclonic status epilepticus” 144143.  The subsequent course is rapid and is characterized by resistant epilepsy, spasticity and blindness 143 144.  Death typically occurs between 6 to 9 years143 145.

3. The juvenile type (Spielmeyer-Vogt-Sjögren Disease), more commonly known as Batten’s disease146, develops between the age of 4 and 10 years.  As with most forms of NCL, visual failure is usually the first symptom, and subsequently seizures, dysarthria and dementia develop, often with severe rigidity144.  A wide variety of seizures types are seen, including myoclonic, tonic-clonic and absence seizures 50.  Optic atrophy, macular degeneration and attenuation of retinal vessels may occur 48.  Life expectancy ranges between 5 and 13 years 144.

4. The adult form (Kuf's Disease) is uncommon and more clinically heterogeneous 145. The onset is typically about the age of 30 years but may range from adolescence142 until the 5th decade147.  It can present as a PME, although cases may also present with a picture of dementia and extrapyramidal or cerebellar disturbance144.  A case of progressive cerebellar ataxia, associated with atrophy and fasciculations, without cognitive impairment and commencing at the age of 43 has also been described148.  Blindness is notably absent, and the optic fundi are normal, although retinal storage of lipofuscin can occur149.  The clinical course from onset to death is approximately 15 years 142

 

1.6.5.1 Diagnosis

Diagnosis presently requires the demonstration of characteristic inclusions by electron microscopy, typically of both skin and muscle143.

 

1.6.5.2 Inheritance

The disorder has AR inheritance. However, one family with adult onset and AD inheritance has been described: 11 members of a four generation family from New Jersey of English origin with PME developed a disorder in their 4th decae characterized by dementia, nystagmus, myoclonus, and associated generalized tonic-clonic seizures.  Progressive cerebellar ataxia was present, and the average duration of illness was 7 years3.

The genetics of the various forms of NCL demonstrates that they are heterogeneous disorders with common pathologic and clinical features (Table 5). 

 

1.6.5.3 Myoclonus

In the AD form of NCL, presenting as PME, myoclonus was associated with tremor and voluntary movement increased the severity of myoclonus and could elicit massive myoclonias3.  In the juvenile form of NCL, myoclonus is described as fragmental, segmental and massive50.  In Kuf’s disease it is described as “elementary or complex, of variable extent, and occurs in irregular paroxysms, sometimes synchronous in all affected muscles, resulting in universal myoclonic discharges”23.

 

1.6.5.4 Pathophysiology

Widespread accumulation of autofluorescent lipopigment inclusions in various organs is a characteristic feature.  The inclusions, which under the electron microscope appear as fingerprint profiles, or as curvilinear and granulomatous bodies, may not always be detected or correctly interpreted, leading to missed diagnoses150.  Early investigators were struck by the widespread nature of abnormal neurons, and Zeman et al stated “in our collective material there was no type of neuron,nor any topographical region consistently exempt from lipopigment accumulation” 144.  However, the most severe nerve cell loss occurs in the cerebellar cortex.

The curvilinear profiles, which are comprised of lamellae showing alternate light and dark lines, are contained in a membrane-bound cytosome, as are fingerprint profiles143.  The lipopigment accumulates at a much earlier age than lipofuscin of aging, and differs from it in that it predominantly contains ceroid.  Pronounced and selective neuronal vulnerability and total loss of small pigment-laden stellate cells, a local circuit neuron, has been demonstrated in the cortex of patients with juvenile neuronal ceroid lipofuscinosis151

 

1.6.5.5 Special Investigations

Assay of urinary sediment dolichols, which are lipid intermediates in the biosynthesis of glycoproteins, shows levels that are ten times higher than controls, and are particularly elevated in the infantile and late infantile forms 152.  Findings of special investigations are outlined in Table 4.

The clinical suspicion of NCL may be supported by electrophysiologic studies with the late infantile and juvenile types having characteristic findings on the EEG, electroretinography and VEP examination48

Table 4      Histological and Immunochemical Diagnosis (After Pearlman and Naidu, 2004)

 

CLN1

CLN2

CNL5

CNL3

CNL4

Tissue

Skin

Skin

Skin

Skin

Skin

Diagnosis

Rectal

Rectal

Rectal

Rectal

Rectal

Electron Micrograph

Conjunctiva

Conjunctiva

Conjunctiva

Conjunctiva

Muscle

Inclusions

Granular

Curvilinear

Curvilinear

Fingerprint/ Curvilinear

Fingerprint/ Granular

Macular degeneration

+

+

+

+

-

EEG-isoelectric

1.5-2 years

-

-

-

-

Visual evoked potential

-

+++

+++

-

-

MRI-brain atrophy

++

+

+

+

+

Hypointensity,thalamus, and basal ganglia T2-weighted images

+

+

+

-

-

 

Diagnosis requires the demonstration of characteristic inclusions by electron microscopy.  These can be found most simply in eccrine secretory cells, as well as in neurons, appendix, skeletal muscle and rectal mucosa143;149;149.  The inclusions take various forms with curvilinear profiles being characteristic of a late infantile NCL, and fingerprint profiles being usual in the juvenile and adult forms, although a number of variations occur143.  In Kuf’s disease there is restricted, rather than generalized, neuronal involvement.  The electron-microscopic evaluation of the skin may miss inclusions, and rectal biopsy has a higher rate of diagnostic success, although it is not commonly studied146.

 

1.6.5.6 Neuropathology

In the dominant form of NCL, neurons from brainstem, frontal cortex, thalamus and cerebellum showed extensive PAS positive granule accumulation with neuronal loss in the substantia nigra.  There was severe loss of Purkinje cells in the cerebellum and diffuse demyelination of the cerebellar and cerebral hemispheric white matter3;3.  In infantile NCL, cortical neuronal loss and astrogliosis are seen, with a reduction in the density of white matter fibres.  The basal ganglia showed similar changes, and there was variable Purkinje cell loss in the cerebellum with the dentate nucleus showing a large number of lipid flakes in degenerated neurons153.  In a case of Kuf’s disease, severe neuronal dropout was observed thoughout the cortex, with remaining neurons loaded with ceroid- lipofuscin granules.  In the basal ganglia, basal ganglia, and the cerebellum had Purkinje cell loss and all neurons in the dentate were distended with ceroid- lipofuscin149.  In a case with onset at age 49, widespread distention of neurons with lipofuscin was noted in the cortex, basal ganglia and spinal cord, with widespread Purkinje cell loss and neuronal loss in the dentate, without evident neuronal loss in the cerebral cortex147

 

1.6.5.7 Genetics

Loci for the various forms of NCL are outlined in Table 5.

Table 5      Genetic Information of NCL Variants (after Schiffman, 2004 and Gardiner, 2002)

Variant

Gene Name

Gene Product

Chromosome

Infantile

CLN1

Palmitoyl protein thioesterase

1p32

Late infantile

CLN2

Tripeptidyl peptidase

11p15

Late infantile Finnish variant

CLN5

"Battenin"

13q21.1-q32

Late infantile variant

CLN6

 

 

Juvenile

CLN3

Endosomal/lysosomal transmembrane protein

16p12

Adult  

CLN4

 

 

 

1.6.5.8 Epidemiology

The NCL group of disorders appears to be panethnic, with a special predilection for the infantile subtype in Finland. The frequency is reported to be as high as 1:12,000 to 1:25,000 live births154, and in Finland the infantile form alone has an incidence of 1:13,000 live births.

 

42. Greenwood RS, Nelson JS. Atypical neuronal ceroid-lipofuscinosis. Neurology 1978;28:710-7.

  143.   Carpenter S, Karpati G, Andermann F, Jacob JC, Andermann E. The ultrastructural characteristics of the abnormal cytosomes in Batten-Kufs' disease. Brain 1977;100 Pt 1:137-56.

  144.   Zeman, W., Donahue, S, Dyken, P, and Green, J. The Neuronal ceroid-lipofuscinoses (Batten-Vogt syndrome). Vinken, P. J. and Bruyn, G. W. (10), 588-679. 1970. Amsterdam, North-Holland.
Ref Type: Serial (Book,Monograph)

  145.   Zeman, W. and Siakotos, A. N. Neuronal ceroid lipofuscinosis. Vinken, P. J. and Bruyn, G. W. (42), 461-468. 1981. Amsterdam, North-Holland.
Ref Type: Serial (Book,Monograph)

  146.   Schiffman, R., Pearlman, E. M., and Naidu, S. Batten Disease. Gilman, S. www.medlink.com . 2004.  MedLink Corporation. 1-14-0004.
Ref Type: Electronic Citation

  147.   Pallis CA, Duckett S, Pearse AG. Diffuse lipofuscinosis of the central nervous system. Neurology 1967;17:381-94.

  148.   Fine DIM, BARRON KD, HIRANO A. Central nervous system lipidosis in an adult with atrophy of the cerebellar granular layer: a case report. J.Neuropathol.Exp.Neurol. 1960;19:355-69.

  149.   Dom R, Brucher JM, Ceuterick C, Carton H, Martin JJ. Adult ceroid-lipofuscinosis (Kufs' disease) in two brothers. Retinal and visceral storage in one; diagnostic muscle biopsy in the other. Acta Neuropathol.(Berl) 1979;45:67-72.

  150.   Carpenter S. Morphological diagnosis and misdiagnosis in Batten-Kufs disease. Am.J.Med.Genet.Suppl 1988;5:85-91.

  151.   Braak H, Goebel HH. Loss of pigment-laden stellate cells: a severe alteration of the isocortex in juvenile neuronal ceroid-lipofuscinosis. Acta Neuropathol.(Berl) 1978;42:53-7.

  152.   Wolfe LS, Ng Ying Kin NM, Palo J, Haltia M. Dolichols in brain and urinary sediment in neuronal ceroid lipofuscinosis. Neurology 1983;33:103-6.

  153.   Klinken-Rasmussen L, Dyggve HV. A case of Late Infantile Amaurotic Idiocy of the Myoclonus Type. Acta Neurol Scand 1965;41:172-86.

  154.   Rider JA, Rider DL. Batten disease: past, present, and future. Am.J.Med.Genet.Suppl 1988;5:21-6.

 

 

References