Brain Pathology Case of the Month - November 2007

DIAGNOSIS:     Kufs' Disease (Adult Neuronal Ceroid Lipofuscinosis).

Further inquiry revealed that the deceased had an older sibling (brother) with similar symptoms who had died some years ago with a similar neurodegenerative condition. An autopsy was not performed.


Neuronal ceroid lipofuscinosis (NCL) is a heterogenous group of neurodegenerative disorders characterized by accumulation of ceroid-lipopigment inclusions in neurones and most other cells (3,14). The typical clinical features include progressive cognitive and motor deterioration and seizures. The early classification of this group of metabolic diseases was based on age of onset and ultrastructural morphology of the lysosomes, and was divided into Infantile, Late-infantile, Juvenile and Adult forms of the disease. The initial separation of subtypes by age of onset is inaccurate as the clinical onset was found to be highly variable (3,12,14). Subsequent knowledge of some of the genetic and enzyme defect for these diseases has enabled reclassification of this disease into 8 main genetic forms designated as CLN1 to 8 (6,14).

The new genetic classification of CLN 1 has presentation mainly in infancy. The CLN 2, 3, 5, 6, 7 and 8 present at various ages but commonly during childhood. The adult form has provisionally been assigned the gene CLN4. However the exact gene locus or loci is yet to be identified.

The CLN1 gene has been mapped to chromosome 1p32 and encodes a lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) (4,12,14). There have been more than 38 mutations reported. The CLN2 has been mapped to chromosome 11p15 and encodes another lysosomal enzyme, tripeptidyl-peptidase 1 (TPP1) (4,12). The gene loci for CLN3, 5, 8 are known but the function of the encoded proteins remains obscure. Curiously, sequence analysis suggests that some of these proteins may be transmembrane proteins (1,2). The CLN 4 gene or genes and the associated metabolic defect responsible for Adult NCL are still largely unknown (3, 4,6,7, 14). Interestingly, two female siblings with adult onset NCL were reported to be compound heterozygotes for mutations of the CLN1 gene (12).

NCL is predominantly a disease of childhood with incidence in the US estimated at 1:12,500 (6). The adult form (Adult neuronal ceroid lipofuscinosis) is extremely rare with less than 100 confirmed cases since it was first reported by Hugo Friedrich Kufs in 1925 (1,4,5).

The mode of inheritance of Adult neuronal ceroid lipofuscinosis (ANCL) or Kufs' disease is usually an autosomal recessive pattern, except for the extremely rare autosomal dominant Parry's form of the disease (6,7,8,11). Two broad clinical phenotypes have been identified (1). The more common phenotype, known as Type A, is characterized by progressive myoclonic epilepsy often diagnosed as a benign form of adult onset generalized epilepsy until features of cognitive decline progressing to dementia appear years later. The epilepsy becomes intractable with time and later there may be pyramidal and extra-pyramidal signs (14). The second phenotype, Type B, presents initially with behavioral changes (6). Later there is progressive dementia often associated with movement disorder including Parkinsonism or facial dyskinesias (1). Seizures are not a prominent feature in Type B (7). Retinal abnormalities with blindness, which are common in the childhood forms of neuronal ceroid lipofuscinosis (Batten's disease), are rarely seen in the adult form (3,5,6,7,10,13). Some cases demonstrate a combination of type A and B features.

The age of onset of ANCL varies from 11 to 50 years (1, 6,14). The course of the disease is slow and leads to death after an average duration of 12.5 years (6). The clinical symptoms of this case fit the more common Type A phenotype.

Reported cases of ANCL have non-specific neuroradiological or macroscopic autopsy findings showing only global symmetrical atrophy of the brain of mild to moderate severity (6). The degree of atrophy is variable among different lobes. There are no distinctive macroscopic features described. This is different from the childhood form of NCL which typically shows striking atrophy with abnormality in the color and texture of the brain on cut sections (6).

Despite the vast heterogenicity in terms of age of onset, clinical symptoms and course, all forms of NCL demonstrate the same histopathological features of abnormal accumulation of PAS and Sudan black B positive inclusions resistant to lipid solvent, present in most neurones and many other cell types (4, 5, 6, 11). The deeper cortical layers III, V and VI are most severely affected (6). The pathology has also been observed in the basal ganglia, thalamus, brainstem and spinal cord anterior horn cells (6). The pathological process is associated with progressive and selective neuronal loss and gliosis with secondary white matter degeneration. Abnormal lysosomes have been demonstrated in eccrine sweat gland, lymphocytes, muscles, liver, kidney, thyroid, pancreas and rectum in cases of childhood NCL but description of the abnormal lysosomes outside the central nervous system in adult cases are poorly characterized (4, 11, 15).

Ultrastructural patterns in NCL can be multiform. In CLN3, CLN 5 and CLN 6 a mixture of rectilinear complexes, fingerprint and curvilinear profiles can be found in neurons. In CLN2, curvilinear profiles predominate; while CLN 1 is characterized by granular osmiophilic deposits (GRODs) (3) and CLN4 is usually associated with mixed type of inclusions (3, 4, 7, 12).

The histopathology and the ultrastructural features present in this case fulfilled the criteria for ANCL (Kufs' disease). Fluorimetric assay of specific enzymes cannot be performed unlike CLN1 and 2 which show no activity for PPT1 and TPP1 respectively. Neither can molecular genetic studies be conducted as the gene responsible for CLN4 (ANCL) has not been identified (3, 4, 6, 7, 14). The advances in molecular and genetic studies of the disease are limited by its rarity and the heterogeneity of the cases. Whether this heterogeneity is caused by different mutations of a single gene or different gene mutations awaits further research.


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  15. Martin JJ, Gottlob I, Goebel HH, Mole SE (1999) CLN 4. Adult NCL. In The Neuronal Ceroid Lipofuscinosis (Batten Disease). Goebel, H.H et al (ed.) Amsterdam: IOS Press (Publishers), 77-90.

Contributed by Thomas Robertson, FRCPA; Anthony E. Tannenberg, FRCPA; Jessie Hiu MPath; Jon Reimers, FRAC

International Society of Neuropathology