Late Infantile Type Research Articles

CEROID‐LIPOFUSCINOSIS. Report of Two Autopsy Cases

Light and electron microscopic examinations were performed on two autopsy cases of ceroid-lipofuscinosis of the juvenile (Case 1) and late infantile (Case 2) types. Much ceroid-lipofuscin (CL) was found in nerve cells throughout the nervous system. In Case 1, CL had also accumulated in thyroid follicular cells, glomerular podocytes, and epithelial cells of the ductus epididymidis, and in the endothelium and smooth muscle of vessels. Electron microscopy showed CL in 5% of peripheral lymphocytes sampled when the patient was alive. In Case 2, an accumulation of CL was found in the vascular endothelial cells of the cerebrum, and Kupffer cells and sinusoidal endothelial cells of the liver. The CL was autofluorescent, and was seen to be composed of electron-dense granules, lipid droplets, lamellar structures, and curvilinear bodies by electron microscopy. Limiting membranes were often found surrounding CL granules. The dolichol level in the cerebral cortex was high in Case 1. Accumulation of CL was found in cells other than nerve cells, although the main signs and symptoms were caused by the involvement of nerve cells. The CL showed various ultrastructural features.

Clinical classification of neuronal ceroid-lipofuscinosis subtypes.

Neuronal ceroid-lipofuscinosis is the most common class of neurodegenerative disease in children. After decades of study, the biochemical basis for this group of diseases continues to elude scientists. One obstacle has been the difficulty in establishing specific criteria for diagnosis. This paper reviews case material from 65 patients referred to the Shriver Center for study from January, 1984 to December, 1986. The late-infantile type was the most commonly encountered (35%) with a mean age-of-onset of 3.1 +/- 0.5 yr. The juvenile type was slightly less frequent (32%) with a mean age-of-onset of 7.8 +/- 4 yr. The infantile type ranked third (23%); age-of-onset 11 +/- 4 months) and the adult form of the disease was the least common (10%; age-of-onset 25 +/- 4 yr). Consistent clinical findings were a progressive decline in mental faculties and seizures, predominantly of the myoclonic type. Neuroradiological changes of cerebral and cerebellar cortical atrophy were common when studies were obtained more than a year after clinical onset. Ataxia was a frequent manifestation in the late-infantile and juvenile types whereas dystonia was unique to the latter. There was a diversity of ultrastructural findings in skin biopsies between and within types. The absence of findings in a few familial cases necessitated sampling a second tissue such as muscle, particularly when the history was suggestive and urine dolichols were high. Elevated urine dolichol levels was a nonspecific but helpful finding.

Dolichol and dolichyl phosphate in the neuronal ceroid-lipofuscinoses and other diseases.

Although, compared to age-matched control samples, nonphosphorylated dolichols are significantly increased in the cerebral cortex of children with the late infantile and juvenile types of neuronal ceroid-lipofuscinosis (NCL), dolichyl phosphates are increased to a much greater extent in infantile, late infantile, and juvenile forms of this disease group. Dolichyl phosphates in the cerebral cortex, expressed as a percentage of the combined nonphosphorylated and phosphorylated compounds, ranged from 59 to 85 (mean 71) in NCL, whereas in the non-NCL disease group the range is 18-36 (mean 25). This marked proportional increase in dolichyl phosphates is not unique to NCL but is also found in the brain of GM1-gangliosidosis and Tay-Sachs disease patients. In the liver from NCL patients, dolichyl phosphates are not a major proportion of the total dolichol compounds (1-9%). However, in the kidney and heart, dolichyl phosphates are again markedly increased, and this is associated with large storage of ceroid. Although to a lesser extent than in NCL, dolichols and dolichyl phosphates are significantly increased over levels in age-matched control samples in the temporal cortex in Alzheimer disease. Our interpretation of these results is that storage in secondary in secondary lysosomes in NCL and the gangliosidoses leads to a decrease in the catabolism of dolichyl phosphate compounds in the Golgi saccules or primary lysosomes.

The Newfoundland aggregate of neuronal ceroid-lipofuscinosis.

We have found a group of individuals with the late infantile, the early juvenile variant, and juvenile neuronal ceroid-lipofuscinosis (NCL) in Newfoundland, an island with a population of 500,000. In the past 25 yr, we have ascertained 44 cases of NCL in 32 sibships: 32 cases of late infantile NCL (LINCL) in 24 sibships, 11 cases of the early juvenile variant in 7 sibships, and one patient with the juvenile form (JNCL). The clinical presentation of the LINCL patients is very characteristic, with onset of seizures at age 2 1/2 to 3 1/2 yr, frequently with drop attacks and myoclonic jerks, followed by mental deterioration, ataxia, visual loss, and death by the end of the first decade. Typical curvilinear profiles are seen on electron microscopy (EM). The second group of patients mainly have the early juvenile variant with onset of seizures at age 5 to 6 yr and fingerprint profiles with occasional curvilinear profiles on EM. However, a child with the juvenile form presenting with blindness was also encountered. In both of these types, death occurs in the second decade of life. There is no overlap of these three clinical forms within sibships, although both late infantile and early juvenile variant types may occur in the same small fishing village. All three forms appear to be inherited as autosomal recessive traits. Although the early juvenile variant has been postulated to represent a double heterozygote between LINCL and JNCL, this cannot be confirmed on the basis of the present study.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuronal ceroid lipofuscinosis in The Netherlands-II.

This paper is a report on Neuronal Ceroid Lipofuscinosis (NCL) in The Netherlands (synonyms: Batten disease, Jansky-Bielschowsky disease, Batten-Mayou disease, Stock-Spielmeyer-Vogt disease). Discussed are the late infantile type with predominant accumulation of lipofuscin in the form of curvilinear bodies (Jansky-Bielschowsky) and the juvenile type with accumulation of lipofuscin in the form of fingerprint- and rectilinear profiles (Batten-Mayou disease and Stock-Spielmeyer-Vogt disease or F-type of NCL).

Clinicopathological differences between juvenile and late infantile metachromatic leukodystrophy

The autopsy report of the juvenile type of metachromatic leukodystrophy is rare. The clinical and pathological difference between the juvenile and the late infantile type of metachromatic leukodystrophy was described. Loss of myelin sheaths was much less in the brain stem and spinal cord in the juvenile type than in the late infantile type, although that of the roots or cranial and spinal nerves was marked similarly in both types. The relationship of these pathological findings to clinical signs and laboratory data was discussed.

On the ultrastructural diversity and essence of residual bodies in neuronal ceroid-lipofuscinosis

In 4 patients with neuronal ceroid-lipofuscinoses (NCL) (3 patients with the juvenile type, 1 patient with the late infantile type), the ultrastructural spectum of residual bodies in the central and peripheral nervous system presented curvilinear profiles in all cases and regions investigated and many more ultrastructural patterms within and beyond regions commonly accessible to biopsy, probably due to age dependence, local tissue and cellular biochemical factors. Sampling from basal ganglia especially yielded combined curvilinear-fingerprint bodies, from peripheral ganglia additional membranous bodies. Residual bodies in NCL were present in almost every cell type, similar to the distribution of regular lipofuscin. Although the classical subgroups of NCL contain electronmicroscopically well defined residual bodies, permitting distinction of the late infantile type from the juvenile type, the ultrastructural differences are more of a quantitative than of a qualitative nature. However, they are not pathognomonic. N.m.r. spectra of ceroid and lipofuscin support the concept of their biochemical similarity, and argue against the proposition that they contain a single major component.

An ultramicroscopic study of the skin in the diagnosis of the infantile and late infantile types of ceroid-lipofuscinosis.

A skin biopsy was carried out in two children suffering from early infantile (Santavuori) and late infantile (Jansky-Bielschowsky) types of ceroid-lipofuscinosis. In both cases cytoplasmic inclusions, identical with those found in neurones, were present in the skin. Skin biopsy thus appears as a simple technique for the diagnosis of the ceroid-lipofuscinoses.

Significance of muscle biopsies in neuronal ceroid-lipofuscinoses.

Muscle specimens obtained at necropsy from four cases of neuronal ceroid-lipofuscinosis (NCL), three of the juvenile and one of the late infantile type, and a muscle biopsy from a fifth patient with the juvenile type of NCL, all showed curvilinear bodies typical of NCL within the muscle fibres. The pigments were autofluorescent. It appears that skeletal muscle is a reliable tissue source for the diagnosis of these disorders by biopsy.

Neuronal storage disorder with chorea and curvilinear bodies.

A clinically unique case of ceroid-Iipofuscinosis is described with a juvenile onset, severe chorea that dominates the clinical picture, absence of retinal changes, and uniform intraneuronal inclusions consisting of curvilinear bodies. Cerebral biopsy was performed and ultrastructural and histochemi-cal studies were made. This case differs clinically from the classic late infantile type of nonglycolipid neuronal storage disorder and it differs clinically and ultrastructurally from the classic juvenile type with pigmentary degeneration of the retina. Several atypical variants without visual loss have been reported, but this case appears morphologically distinct from the few cases with a dystonic form recently described ultrastructurally. It supports the notion of nosologic heterogeneity among the nonglycolipid neuronal storage disorders.

Neuronal ceroid-lipofuscinosis, a type of amaurotic family idiocy. Clinical and pathological study of four cases.

Neuronal ceroid-lipofuscinosis (NCL) is a recent term, proposed for acurate designation of the late-onset types of Amaurotic Family Idiocy (AFI). Histopathology shows ubiquitous intraneuronal accumulation of lipopigments, being the most important factor for characterization of the entity at present time. Biochemical changes and pathogenesis are obscure. NCL is in contrast to the infantile type of AFI (Tay-Sachs disease), in which intraneuronal accumulation of gangliosides (sphingolipids) is due to the well known deficiency of a lysosomal enzyme. The authors report on four cases of NCL, two brothers of the late infantile (Jansky-Bielschowsky) type and a brother and a sister of the juvenile (Spielmeyer-Sjögren) type. One autopsy and three cortical biopsies revealed moderate to severe distention of the neurons by lipopigment, with nerve cell loss, gliosis and cerebral atrophy. Lipopigment was also increased in liver, heart and spleen. The patients were the first in Brazilian literature in whom the storage material was identified as lipopigment by histochemical methods. A brief summary of the clinical features of NCL is presented, and relevant problems are discussed, concerning interpretation of the nature of the storage material, and significance of the disease for gerontological research.

Involvement of Sural Nerve in Neuronal Ceroid-Lipofuscinoses: Report of Two Cases

Findings in sural nerve biopsies in two patients with neuronal ceroid lipofuscinosis are described. In Schwann-cells and in smooth muscle cells of vessels curvilinear- and fingerprintmaterial were demonstrated. The report discusses the significance of these findings. The clinical findings were in agreement with a diagnosis of late infantile and juvenile type respectively. Ultrastructurally there were signs of transitions between the two types of inclusion. The place of sural nerve biopsy in the range of diagnostic procedures in progressive neurological diseases in discussed.

Infantile type of so-called neuronal ceroid-lipofuscinosis. Histological and electron microscopic studies.

Autopsy reports are presented of three cases of a rapidly progressive encephalopathy with clinical onset around one year of age, early amaurosis, and microcephaly. Convulsions were few or absent. The disorder led to an extraordinary degree of brain atrophy, due to total loss of neurons from the cerebral and cerebellar cortex, and an advanced degree of neuronal destruction in most subcortical centres. The giant cells of Betz and the primary motor and sensory neurons were notable exceptions. The surviving neurons, other neuroectodermal cells, and a number of extraneural cell types showed accumulation of autofluorescent sudanophilic granules, resistant to lipid solvents, in their cytoplasm. Ultrastructurally, these granules were of the residual body type, consisting of membrane-bound conglomerations of spherical globules 0.2–0.5 μm in diameter, with a homogeneous, finely granular internal structure. These lesions were associated with a pronounced astrocytic and mesenchymal reaction with the presence of large numbers of phagocytic cells in the grey matter of the CNS and, to a lesser extent, in other tissues. In addition, there was almost total loss of myelin from the brain, apparently due to Wallerian degeneration. The characteristic clinical, histological and ultrastructural features differentiate this condition from other progressive encephalopathies of the age group in question, including the late infantile type of the Batten-Vogt syndrome. Recent ultrastructural and biochemical findings indicate that the disease of our patients is identical with the progressive encephalopathy with disturbed polyunsaturated fat metabolism described by Hagberget al. (1968).

Cerebral lipids in a case of systemic Gm2-gangliosidosis of a late infantile type.

Abstract—Quantitative analyses performed on the lipids of cerebral grey matter from brains of a normal child and a child with Tay‐Sachs (T‐S) disease were compared with such analyses on the brain of a 6‐year‐old, non‐Jewish male with systemic GM2‐gangliosidosis of a late infantile type (GM2‐LI). Analysis of gangliosides showed a 3·5‐fold increase of total gangliosides in the GM2‐LI brain and a six‐fold increase in the T‐S brain, compared to normal brain. Both pathological brains had similar distribution patterns for gangliosides, with the GM2‐ganglioside component constituting more than 80 per cent of the total. Lipid components in the T‐S brain were below normal values except for lecithin and cholesterol, while in the GM2‐LI brain there were increases in sulphatides, cerebrosides, sphingomyelin and cholesterol. Approximately twice as much ceramide trihexoside was present in the T‐S brain as in the GM2‐LI brain, and none could be detected in the normal brain. The clinical, pathological and biochemical data support the conclusion that this case represents a new variant of systemic late‐infantile gangliosidosis in which there is an accumulation of the GM2‐ganglioside like that in Tay‐Sachs disease.

Hexosaminidase activities in a case of systemic GM2 gangliosidosis of late infantile type.

SummaryAn unusual systemic GM2 gangliosidosis of late infantile type was shown to have high levels of hexosaminidase activity in brain and liver. It, therefore, differs from another GM2 variant of late infantile type reported by Sandhoff et al. (2), in which hexosaminidase activity was absent.Addenum. Okada and O'Brien reported that the isoenzyme hexosaminidase A was absent in TSD tissue (6). The percentage of hexosaminidase A and B in brain extracts from the present case and from a TSD and control case were analyzed by acrylamide gel electrophoresis and quantitative fluorometric scanning using 4-methylumbelliferyl-2-acetamide-2-deoxy-β-D-glucopyranoside as substrate. In the present case the A fraction comprised 40% of the total hexosaminidase activity in contrast to 60% in a control and 0% in TSD brain.

Sphingomyelinase in normal human spleens and in spleens from subjects with Niemann-Pick disease

This paper describes the purification and some of the properties of an enzyme from human spleen that catalyzes the hydrolysis of sphingomyelin with the formation of ceramide and phosphoryl choline. The enzyme, which is located in the subcellular particulate fraction that sediments between 700 and 8500 g, is readily made soluble and has been partially purified. Its pH optimum is between 4.5 and 5.0. It is unaffected by divalent cations, chelating agents, and sulfhydryl reagents, but is inhibited by phosphate. The enzyme attacks sphingomyelin and dihydrosphingomyelin, but is inactive toward sphingosine phosphoryl choline, O-acetylsphingomyelin, and lecithin. In some of its properties, the enzyme from human spleen is different from the previously studied sphingomyelinase from rat tissues. The enzyme is absent or markedly reduced in spleens from patients with classical and visceral varieties of Niemann-Pick disease, but is present in normal amounts in the late infantile type of the disease. In the present study another enzyme, this one magnesium-dependent, capable of catalyzing the cleavage of sphingomyelin has been detected in the spleens of patients with the classical form of Niemann-Pick disease. Some implications of these findings for theories of the metabolic defect in Niemann-Pick disease are discussed.

A Case of Late Infantile Type of Amaurotic Family Idiocy

Histochemistry of primary cerebral lipidosis is not a completely explored out field of research. Many points of ambiguity and lack of information remain in literatures which cause discrepancy of opinions among authors. We recently experienced one case of late infantile form of amaurotic family idiocy (Bielschowsky), the clinical and autopsy record of which is here by preliminarily reported.

AMAUROTIC FAMILIAL IDIOCY IN IDENTICAL TWINS

Since the original descriptions by Tay in 1881 and Sachs in 1887 of amaurotic familial idiocy in infants, a great deal of knowledge has been added to the subject, and it is now recognized that this condition exists not only in the form of (<i>a</i>) infantile amaurotic familial idiocy as originally described but in three additional forms, namely (<i>b</i>) the late infantile type, (<i>c</i>) the juvenile type and (<i>d</i>) the adult type.¹As the cases reported in this paper are instances of the classic form of amaurotic familial idiocy, to which the name Tay-Sachs disease has been given, a brief description of the disease will be limited to this form only and the others will be omitted as being beyond the scope of this presentation. Tay-Sachs disease is uncommon, though not rare; and while cases have been reported for the past fifty years, a search of the literature available

A Case of Amaurotic Family Idiocy, Late Infantile Type (Bielschowsky), with Clinical Picture of Decerebrate Rigidity. (Arch. of Neur. and Psychiat., December, 1926.) Hassin, G. B.

<i>A Case of Amaurotic Family Idiocy, Late Infantile Type (Bielschowsky), with Clinical Picture of Decerebrate Rigidity. (Arch. of Neur. and Psychiat., December</i>, 1926.) <i>Hassin, G. B.</i>

A CASE OF AMAUROTIC FAMILY IDIOCY

In contrast to the great number of clinical and pathologic reports on the infantile (Tay-Sachs) type of amaurotic family idiocy, reports on the juvenile and especially the so-called late infantile (Bielschowsky) types are scarce. This is most likely due to the fact that the last two varieties are rare and do not present such a clear cut clinical picture as the classic form of Tay-Sachs disease. For this reason also they are usually not recognized by clinicians but are accidental observations postmortem. Described first by Jansky, 1 cases of the late infantile variety of amaurotic family idiocy have been recorded by Schob, 2 Brodmann 3 and Marinesco, 4 and have been especially well studied by Bielschowsky. 5 The case here recorded is remarkable not only for its pathologic but also for its clinical features, which were those of decerebrate rigidity, and for the fact that the disease occurred in one