Neuronal Ceroidlipofuscinoses

Neuronal ceroid-lipofuscinoses (NCLs) are a group of diseases characterized by neurological symptoms and the accumulation of autofluorescent waxy lipopigments within the lysosomes of neurons and other cells. The disorders are linked to a number of celebrated names in neurological history, including Batten, Jansky, Bielschowsky, Santavuori, and Kuf, each of whom described clinical variants of these multidimensional disorders. The conglomerate term neuronal ceroid-lipofuscinoses was coined by Zeman and Dyken in 1969 to emphasize the neurological involvement, clinically and pathologically. [ii In 1995, a classification of seven forms of NCLs was developed to consolidate earlier clinical and genetic descriptions ( ..Table,..30-1 ).

Pathogenesis and Pathophysiology. In the NCLs, waxy lipopigments, composed of ceroid, lipofuscin, and excessive amounts of a protein identified as "subunit c," accumulate in neurons and non-neuronal tissue. All subsequent symptoms are based on this accumulation, which activates cellular dysfunction and death in differently maturing groups of neurons (see T§ble..,3.0-1 ). It has been speculated that cellular death is apoptotic. y A combination of metabolic and mechanical factors also lead to the dysfunctional state. The lipopigments accumulate first in the larger neurons and tend to cluster around the axonal hillock. Inert lipopigments and debris progressively accumulate in an area rich in inhibitory synapses. Thereafter, the waxy pigments gradually spread to other parts of the neuron, ultimately involving the rest of the cell body while sparing the dendritic tree. Progressive swelling of the neuron occurs, followed by cellular death, subsequent disruption of the cell membranes, extracellular extrusion of debris, and its accumulation within scavenger cells. By this time, smaller neurons are involved as well as glia, endothelium, and fibrocytes. Lipopigments accumulate to a mild extent in almost all cells of the body, including lymphocytes, eccrine cells, fibroblasts, endothelial cells, ganglion cells of the rectum, and conjunctival cells. This observation permits detection of the "diagnostic" cytosomes without the need for brain biopsy. It must be emphasized, however, that the absence of such material in non-neuronal sites does not exclude the diagnosis, and the presence of similar osmophilic bodies does not establish it.

The slow process of waxy pigment accumulation first in the axonal hillock may account for the epileptogenesis that is often present, particularly in the late infantile (NCL 2)






Enzyme Deficiency

Prominent Cytosome


Age of Onset

Major Signs


Batten's(juvenile chronic form)

Not known


Autosomal recessive

4-12 yr juvenile

Blindness, seizures, dementia; mixed pyramidal and extrapyramidal signs


Bielschowsky's (acute late infantile)

Not known


Autosomal recessive


Seizures, followed by acute decline in motor and mental functions with vegetative state in 2 years


Santavuori's (acute infantile)

Not known


Autosomal recessive

Infants, 3-12 months

Fulminating psychomotor deterioration, seizures


Kuf's (adult recessive)

Not known


Autosomal recessive


Chronic motor, cerebellar, or extrapyramidal signs and mental deterioration, seizures


Boehme's (adult dominant)

Not known


Autosomal dominant


Seizures, no retinopathy


Lake's (early juvenile)

Not known


Autosomal recessive

Early juvenile, 4-5 yr

Mixed pattern of signs of NCL 1 and 2



Not known


Autosomal recessive


Retinopathy, mental and motor deterioration

and juvenile (NCL 1) forms. It is speculated that classic seizures are precipitated by an overriding glutaminergic state caused by cancellation of the inhibitory influences at the axonal hillock. Hyperglutaminergic states may also lead to more rapid loss of other neurological functions.

All NCLs are autosomal recessive except for the adult autosomal dominant or Boehme form of the disease. It is notable that the proposed gene defects are different for the different forms of the disorder. In NCL 1, a genetic defect exists in chromosome 16p12; the early juvenile, or NCL 6, form is carried on chromosome 13 (13p31-32); the infantile form (NCL 3) is carried on the first chromosome (1q32); and the genetic defect for Bielschowsky's disease (NCL 2) is not known, but is definitely not located on the first, thirteenth, or sixteenth chromosomes. The loci for the two adult forms (NCL 4 and NCL 5) and the many atypical cases (NCL 7) are not known. Furthermore, it has been shown in some examples of classic juvenile NCL that no abnormalities are present on the sixteenth chromosome. [3

Epidemiology and Risk Factors. These genetic diseases are probably present in all ethnic and racial groups around the world. One series in the United States found that NCL 1 was the most common form, followed by NCLs 2, 3, 7, 4, 6, and 5 (see T§ble..,3.0-1 ), in that order. These data agree with experiences in Germany, Britain, the Netherlands, and Sweden. In Poland, on the other hand, the late infantile (NCL 2) form is encountered more frequently. This may possibly hold true for the other Eastern European countries as well. In Finland, the more common type is the acute infantile Santavuori form. It is so common there and so rare elsewhere that it is often called the Finnish form. In Saudi Arabia, the vast majority of NCL patients suffer from a form that is relatively uncommon in the United States, the early juvenile NCL 6.

Clinical Features and Associated Disorders. The most frequent of the many syndromes is NCL 1 or Batten's disease, the classic juvenile chronic form. Onset, which includes neurological dysfunction, usually occurs between the ages of 5 and 15 years. [4 The patient may be referred initially to an ophthalmologist or psychiatrist. By age 10, the patient is most often referred to a neurologist. The obvious behavioral symptoms have progressed from a learning deficiency to frank dementia. Likewise, visual dysfunction has usually progressed to blindness. There is a slow and steady progression of neurological symptoms. Three stages of clinical deterioration occur. The first phase involves visual and behavioral disturbances, and the middle phase consists of seizures and motor dysfunction related to a mixture of pyramidal and extrapyramidal symptoms. In the terminal phase the preceding symptoms may become much worse, and there may be changes in affect and motor signs including myoclonus. The three phases are steadily progressive and form an overall monophasic illness that distinguishes NCL 1 from the other disorders described in this chapter.

As a general rule, phase one lasts from 6 months to 5 years, phase two from 2 to 10 years, and phase three from 1 to 10 years. This results in a life expectancy that ranges from 3 to 25 years after the initial visual-neurological symptoms are noted. The course of the disease is generally directly proportional to control of the seizures. Once seizures become refractory and frequent, the course proceeds rapidly downhill to a vegetative state.

The rather slowly progressive course of NCL 1 is quite different from the more rapidly progressive NCL 2 (Bielschowsky's disease). In this acute, late infantile form, the period from the initial neurological symptoms to a severe vegetative state is seldom longer than 2 years. In NCL 2, on average, the first symptom seldom appears after 2 years of age.y This condition's hallmark is a seizure disorder that begins precipitously, progresses rapidly, and ultimately becomes refractive to all anticonvulsant medications. The initial seizures are usually described as drop attacks, myoclonic, partial, or generalized seizures, although nearly all types of seizure often occur within a short period of time. In this rapidly developing disorder, severe intellectual and mental deterioration is seen. The child becomes nonambulatory, usually in the first year of the disease. During this time, vision is progressively lost, yet because of the general loss of neurological function, such an isolated sign is often not recognized. Compared to patients with the juvenile form, a characteristic retinopathy occurs with striking retinal artery attenuation, patches of retinal atrophy, and symmetrical macular granular degeneration.

The third most frequent form of NCL in the United States is the rapidly progressive infantile form. The onset occurs within the first year of life, after a symptom-free period between birth and 3 months of age. Then a sudden and dramatic psychomotor collapse occurs with loss of neurological and visual functions. The collapse may or may not be associated with drug-refractory seizures or severe myoclonus.

Kuf's adult-recessive form of NCL (NCL 4) has two major clinical presentations. '5] One begins with late-onset epilepsy and subsequent subacute loss of mental functions but relative preservation of motor functions. Another clinical form of NCL 4 is marked by predominant motor dysfunction. This dysfunction may become manifest as pure cerebellar ataxia or progressive rigidity.

In contrast to other NCLs, Boehme's disease (adult- dominant NCL 5) is transmitted by autosomal dominant inheritance. Onset of symptoms usually begins around age 30, and this form can be practically indistinguishable from the epileptic form of NCL 4. The NCL 5 syndrome is associated with epilepsy in all instances, and it is important to emphasize that neither nCl 4 nor NCL 5 shows retinal disturbance. This adult-onset condition remains stable for a short time and then becomes progressively worse until seizures become refractory. The syndrome is associated with progressive behavioral and mental dysfunction eventually ending in dementia. The ability to ambulate is lost because of the combination of pyramidal and extrapyramidal dysfunction. Both NCL 4 and NCL 5 are characterized pathologically by excessive amounts of aging lipofuscin and osmophilic granular material in the neurons and ganglion cells in non-neuronal tissues. '<6

The early juvenile form of NCL, (NCL 6), formerly considered a transitional form, '1 has clinical features that overlap those of the late infantile and juvenile forms. There may be fewer retinal abnormalities than in NCL 1 or NCL 2, but other features characteristic of both the juvenile and late infantile forms are seen. Onset occurs between 4 and

8 years of age, and the course is subacute compared to the chronic juvenile and acute late infantile forms of the disease.

Differential Diagnosis. The most important step in the differential diagnosis is to identify the order of the characteristic symptoms, taking into account the fact that the retinal picture may be of greatest importance. This evaluation separates the retinal NCLs (NCL 1, 2, 3, 6, and some 7) from the nonretinal NCLs (NCL 4, 5, and some 7). The differential diagnosis for the group includes all neurodegenerative diseases characterized by epilepsy, blindness, motor failure, and dementia, including the gangliosidoses and sphingomyelinoses.

Evaluation. A battery of laboratory tests is important in the workup of NCL patients. Neuroimaging studies show abnormalities characteristic of the type and stage of disease and demonstrate that most NCLs are ultimately atrophic poliodystrophies involving the cerebral cortex. Certain unique types such as the spinocerebellar form show selective involvement of the cerebellum in which autofluorescent storage material accumulates in Purkinje cells. M In NCL patients with epilepsy, electroencephalography (EEG) shows epileptogenic patterns. Electroretinograms are decreased or absent in patients with the retinal NCL types. Particularly in NCL 2 (and NCL 6), exaggerated evoked potential responses are seen, especially following tactile or somatosensory stimulation. Evoked potential exaggeration also occurs in some other NCLs.

Clinical and histopathological evaluations are essential to make the specific diagnoses. Ultrastructural cellular cytosome alterations are seen on electron microscopy in extracerebral tissue such as ganglion cells in the rectal submucosa, in eccrine cells and fibrocytes of the skin, in endothelial cells in vessels, in lymphocytes in the peripheral blood, and in conjunctival cells. Extracerebral evaluation may not be entirely infallible. Many current diagnostic problems stem from confusion about the cytosomes themselves. Osmophilic inclusions occur frequently as an artifact of tissue preparation for electron microscopy and do not always represent the diagnostic inclusion of the NCL. Four suggestive cytosomes are important, and two of these are diagnostic. The osmophilic fingerprint cytosomes are highly characteristic as lymphocytic inclusions in NCL 1. The second diagnostic osmophilic cytosome is the curvilinear body, which characterizes NCL 6 and many forms of NCL 7. These are not seen in NCL 4 or NCL 5. The third important ultrastructural cytosome is the granular cytosome or GROD, which is encountered in all forms of NCL but is the dominant cytosome in NCLs 3, 4, and 5. The least diagnostic cytosome is the classic lipofuscin body.

A large proportion of the storage material involved in NCL consists of the mitochondrial protein called subunit c. This material is found in very high quantities in NCL 2 but is also seen in increased amounts in NCL 1 and NCL 6. Urinary dolichols are also increased in the NCLs but are higher than normal in many other conditions as well.

Management. Symptomatic treatment, particularly proper anticonvulsant therapy, is important in all NCL disorders. Sodium valproate has been used with success. Antioxidants may improve the symptoms in some cases, and trials of these medications have been undertaken in patients with NCLs 1, 2, 3, and 6. It has been suggested that long-term antioxidant treatment and vitamin E may delay loss of intellectual and motor function and may be helpful in seizure control as well. Extrapyramidal symptoms such as dystonia and myoclonus are treated symptomatically, and behavioral modification techniques may be useful, particularly in the chronic forms. If the symptomatology is of long standing, palliation of the symptoms may be extremely useful in supporting a long and often useful life for the patient. School placement and modified educational programs are important in patients with the chronic forms of disease.


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