NOVEMBER 2007 CASE 2: 53‐YEAR‐OLD MAN WITH RAPID COGNITIVE DECLINE

CLINICAL HISTORY

The patient was a 53‐year‐old man who presented with confusion and amnesia and subsequently suffered rapid progressive cognitive decline over the next few weeks associated with myoclonic jerks. His condition did not improve and he expired just over 3 years after presentation. The patient had a past medical history of adult onset generalized epilepsy beginning the third decade of life. Initially, the cognitive decline, myoclonic jerks and epilepsy were not thought to be linked and a clinical diagnosis of Creutzfeldt‐Jakob disease was made based on the age of onset, symptoms, and the aggressive nature of the disease.

GROSS AND MICROSCOPIC DESCRIPTION

Autopsy restricted to the brain was performed. The brain showed moderate global atrophy with hydrocephalus ex‐vacuo. There was mild thickening of the basal leptomeninges and an incidental small old contusion to the left temporal lobe. Apart from these changes, there was no other abnormality seen macroscopically.

The light microscopy examination of the hematoxylin and eosin stain sections showed neuronal ballooning change, with affected neurons having a finely granular, pale basophilic tinctorial hue (Figure 1A). This change was most evident in the brainstem, in particular the cranial nerve nuclei and reticular formation. The cerebellum exhibited patchy Purkinje cell loss with Bergmann gliosis. The basal ganglia, nucleus basalis of Meynert, and hypothalamus showed neuron loss and gliosis with residual neurons also showing ballooning change. The hippocampus and amygdala showed ballooned neurons but no discernible neuron loss. The thalamus was relatively spared with only rare neurons showing mild accumulation of intracytoplasmic material. The cortex showed variable ballooning change and neuron loss, most evident in laminae V and VI. The insular cortex appeared the most severely affected.

Figure 1.

Histochemical stains revealed affected neurons to be Periodic acid‐Schiff (PAS) positive after diastase treatment (Figure 1B). The intracytoplasmic material did not show demonstrable autofluorescence.

ULTRASTRUCTURAL STUDY

Ultrastructural examination demonstrated that the ballooned neurons contained excessive and abnormal lipofuscin lysosomal vacuoles containing granular (Figure 2A), rectilinear (Figure 2A) and fingerprint profiles (Figure 2B) in association with dense osmiophilic (presumably lipid) masses. (DIAGNOSIS AND DISCUSSION ON NEXT PAGE)

Figure 2.

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.

DISCUSSION

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 eight main genetic forms designated as CLN1–8 6, 14.

The new genetic classification of CLN1 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 CLN4 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, ANCL) is extremely rare with less than 100 confirmed cases since it was first reported by Hugo Friedrich Kufs in 1925 1, 4, 5, 8.

The mode of inheritance of 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, 9, 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 neurons 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, 9, 11.

Ultrastructural patterns in NCL can be multiform. In CLN3, CLN5 and CLN6, a mixture of rectilinear complexes, fingerprint and curvilinear profiles can be found in neurons. In CLN2, curvilinear profiles predominate; while CLN1 is characterized by granular osmiophilic deposits (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.

ABSTRACT

Kufs’ disease (adult neuronal ceroid lipofuscinosis) is a rare form of neurodegenerative lysosomal storage disease, the genetic basis of which remains obscure. We present a case of a 53‐year‐old man with a long history of adult onset epilepsy who presented with confusion and amnesia, and subsequently underwent rapidly progressive cognitive decline associated with myoclonic jerks. The clinical diagnosis was Creutzfeldt Jakob disease. However, autopsy brain examination revealed changes of Kufs’ disease (Adult onset neuronal ceroid lipofuscinosis, or ANCL, also known as CLN4). No specific gross abnormalities were found but light microscopic examination revealed widespread neuronal ballooning and histochemical staining showed neuronal accumulation of PAS‐positive material. Ultrastructural examination demonstrated excessive and abnormal lipopigment lysosomes typical of neuronal ceroid lipofuscinosis. The typical clinical and pathologic features of the Kufs’ disease are discussed and the classification of neuronal ceroid lipofuscinosis is reviewed.