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PubMed2024

Further description of the phenotypic spectrum of neuronal ceroid lipofuscinosis type 11.

PURPOSE: Ceroid lipofuscinosis type 11 (CLN11) is a very rare disease, being reported in only 13 unrelated families so far. Further reports are necessary to comprehend the clinical phenotype of this condition. This article aims to report 9 additional cases of CLN11 from 9 unrelated Latin American families presenting with relatively slow disease progression. METHODS: This was a retrospective observational study including patients with CLN11. Patients were identified through an active search for granulin precursor gene (GRN) pathogenic variants across the entire database of next-generation sequencing of a commercial laboratory and by contacting attending physicians to check for clinical and radiologic findings compatible with a neuronal ceroid lipofuscinosis phenotype. RESULTS: Nine CLN11 patients from unrelated families were evaluated. Age of onset varied between 3 to 17 years. The most common findings were visual impairment, cerebellar ataxia, seizures, myoclonus, and cognitive decline. One patient had a previously unreported finding of cervical, perioral, and tongue myoclonus. Most of the patients were able to walk unassisted after an average of 14.2 years (SD 4.76 y) from disease onset. CONCLUSION: We describe 9 new cases of a very rare type of neuronal ceroid lipofuscinosis (CLN11) from Latin America with a recurrent p.(Gln257ProfsTer27) and a novel p.(Cys83Ter) nonsense variant. Our findings suggest that a slowly progressive neuronal ceroid lipofuscinosis might be a clue for the diagnosis of CLN11.

Humans↗
PubMed1994

Ceroid granulomas of the gallbladder. A clinicopathologic study of nine cases.

Nine cases of ceroid granulomas of the gallbladder were found in 125 surgically excised gallbladders during a one year review (7.35%), corresponding to an estimated incidence of 2.1 cases per 100,000 inhabitants per annum. Seven patients were under 50 year of age. Four patients presented symptoms and signs of chronic cholecystitis. However, in five cases, a mass in the right hypochondrium was palpated, mimicking a carcinoma of the gallbladder. The lesion was characterized by intramural or mucosal yellow-brown nodules composed of ceroid-laden histiocytes. The presence of intramural destructive necrosis in one case suggests that ceroid granulomas of the gallbladder have the potential of developing fistulae or perforations. Rupture of the Rokitansky-Aschoff sinuses and mucosal ulceration with intramural liberation of bile were implicated in the pathogenesis. The characteristic microscopic appearance, as well as the ceroid nature of the granules revealed by histochemical and ultrastructural studies, support the view that ceroid granulomas of the gallbladder should be recognized as a distinct histo-pathological entity. It is important to recognize this lesion as it can be mistaken for carcinoma and may be responsible for serious complications, such as fistulae or perforation.

Adult↗
PubMed2001

Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood.

Neuronal ceroid lipofuscinoses (NCLs) are the most common hereditary neurodegenerative diseases of childhood. The infantile form, INCL, is caused by lysosomal palmitoyl-protein thioesterase (PPT) deficiency, which impairs the cleavage of thioester linkages in palmitoylated proteins, preventing their hydrolysis by lysosomal proteinases. Consequent accumulation of these lipid-modified proteins (constituents of ceroid) in lysosomes leads to INCL. Because thioester linkages are susceptible to nucleophilic attack, drugs with this property may have therapeutic potential for INCL. We report here that two such drugs, phosphocysteamine and N-acetylcysteine, disrupt thioester linkages in a model thioester compound, [14C]palmitoyl approximately CoA. Most importantly, in lymphoblasts derived from INCL patients, phosphocysteamine, a known lysosomotrophic drug, mediates the depletion of lysosomal ceroids, prevents their re-accumulation and inhibits apoptosis. Our results define a novel pharmacological approach to lysosomal ceroid depletion and raise the possibility that nucleophilic drugs such as phosphocysteamine hold therapeutic potential for INCL.

Acetylcysteine↗
PubMed1997

Modulation of nerve growth factor internalization by direct interaction between p75 and TrkA receptors.

While the central role played by TrkA in nerve growth factor (NGF) signalling has been established by dissecting its signal transduction pathways, insight into the mechanism of action of p75LNR, the low-affinity neurotrophin receptor, has only recently been achieved. The relative contribution of p75LNR and TrkA to the constitution of high-affinity receptors for NGF and, similarly, with TrkB an TrkC to the formation of those for other neurotrophins, is presently under debate. Some form of collaboration in mediating neurotrophin activities has been observed between the Trk and p75LNR receptors, but only recent indirect evidence indicates a molecular interaction. In the present work, we have ectopically coexpressed p75LNR and TrkA in Sf9 insect cells by using baculovirus vectors, and show a direct association between the two NGF receptors. In addition, we show that the intracellular and extracellular domains of both receptors contribute to this interaction. Finally, we demonstrate that NGF becomes endocytosed in TrkA-expressing cells but not in p75LNR-expressing cells, and that such function can be modulated by the presence of the intracellular domain of p75LNR receptor.

Animals↗
PubMed1992

Ceroid lipofuscinosis in the border collie dog: retinal lesions in an animal model of juvenile Batten disease.

Ceroid lipofuscinosis, an inherited disorder of lipopigment accumulation, was identified in a group of Border Collie dogs. The dogs developed mental, motor, and visual signs between age 15 and 22 months and progressed rapidly to severe neurological disease. The principal signs were blindness and gait and behavioural abnormalities with progressive dementia. Lipopigment accumulation was severe in neurones and glial cells of the central nervous system and was present in some visceral cells. Inclusions with variable ultrastructure were common in all cells of the retina, but the pigment accumulation did not damage the retinal architecture. The cytoplasmic inclusions were granular, sudanophilic, eosinophilic, and autofluorescent. Ultrastructural morphology varied, but fingerprint and curvilinear patterns predominated. The retinal lesions in the Border Collies were similar to those in English Setters with ceroid lipofuscinosis, but were much less severe than in juvenile human ceroid lipofuscinosis. This disorder bears a close resemblance to ceroid lipofuscinosis in English Setters and is another useful model for Batten's disease.

Animals↗
PubMed1995

Free radicals, anticonvulsants, and the neuronal ceroid-lipofuscinoses.

The relationship between free radicals and scavenger enzymes, and the disorders called the neuronal ceroid-lipofuscinoses, has long been an argumentative one. Recent evidence would seem to support the fact that such a relationship might exist but that it is indirect. The relationship does not seem due to an inborn error of free radical scavenger enzyme metabolism. Anticonvulsants play a role, as they influence free radical generating systems. At this juncture, no one has studied the relationship of anticonvulsant therapy, neuronal ceroid-lipofuscinosis, and the free radical-scavenging enzyme system, and their interplay. We have studied a large number of patients with epilepsy who are on either monotherapeutic or polytherapeutic regimens of most of the common anticonvulsants. We have found excessive free radical production in many of these patients, ranging from minor effects in the simpler anticonvulsants when used monotherapeutically, to more complex changes in polytherapeutic combinations. Likewise, we have found subtle and inconsistent findings in the free radical-scavenging enzyme system in a variety of examples of neuronal ceroid-lipofuscinosis. When refractory seizure disorders stimulate the vigorous use of polytherapy with a variety of free radical-facilitating anticonvulsants, free radical production becomes deleterious. Likewise, in certain types of neuronal ceroid-lipofuscinosis, polypharmacy with anticonvulsants, by enhancing the production of free radicals or suppressing scavenging enzymes, tends to be deleterious and induces a worsening in the disease process.

Adolescent↗
PubMed1995

Hematopoietic cell transplantation in fetal lambs with ceroid-lipofuscinosis.

Hematopoietic cells from the liver of normal 45-48-day-old fetal lambs (Hb type AA) were transplanted intraperitoneally into 58-60-day-old recipient fetuses (Hb type BB). The recipient fetuses resulted from mating homozygous ceroid-lipofuscinosis affected males with heterozygous, phenotypically normal, females. The sex of the donor fetus was also recorded. At age 2 1/2 months the recipient lambs with ceroid-lipofuscinosis were diagnosed by histopathology of brain biopsies. Monitoring of blood and bone marrow cells showed that an average of 9% of blood cells in ceroid-lipofuscinosis affected recipients were of donor origin. No differences were evident in the clinical course of disease, brain weight, or histopathology of organs between transplanted and non-transplanted lambs with ceroid-lipofuscinosis. Under the conditions of this experiment, transplantation of fetal hematopoietic cells was not beneficial.

Animals↗
PubMed1993

Motor neuron degeneration of mice is a model of neuronal ceroid lipofuscinosis (Batten's disease).

Pathological studies of mice homozygous for the motor neuron degeneration (Mnd) mutation show abnormalities similar to those of the human neuronal ceroid lipofuscinoses: sudanophilic, autofluorescent intraneuronal inclusions that are immunoreactive with antibodies to subunit c of mitochondrial ATP synthase. Ultrastructurally, the inclusions have the pentalaminar structure characteristic of some form of human neuronal ceroid lipofuscinosis and of canine and ovine models of neuronal ceroid lipofuscinosis. Similar inclusions are observed in many somatic organs and in the retina, which develops photoreceptor degeneration. This mutation, previously considered a model of amyotrophic lateral sclerosis, may be a useful model for molecular and genetic studies of human neuronal ceroid lipofuscinosis because mice have been well characterized genetically. Since they are inexpensive to breed and maintain, they can also be used to test therapeutic interventions.

Animals↗
PubMed1993

Successful DNA-based prenatal exclusion of juvenile neuronal ceroid lipofuscinosis.

A family with two siblings, 10 and 8 years old, both with clinical and ultrastructural evidence of juvenile neuronal ceroid lipofuscinosis is described. The family was found to be informative for the restriction fragment length polymorphisms (RFLPs) detected by the probes pCJ52-95M1 (locus D16S148) and pCJ52-94T1 (locus D16S159) flanking the juvenile neuronal ceroid lipofuscinosis locus, CLN3. The parents were both heterozygous using these probes, while their two children with juvenile neuronal ceroid lipofuscinosis were both homozygous. Chorionic villi analysis showed that the fetus was heterozygous and had inherited the one allele of the mother which was not found in the two siblings. This suggested that the fetus had derived one healthy allele from the mother, the risk for a double crossing-over being less than 1 per cent. Electron microscopy showed no fingerprint inclusions in chorionic villi. The child was investigated at 6 months of age and found to be healthy, as new fingerprint inclusions were found at electron microscopy and no vacuolated lymphocytes were found in the blood smear. Due to the risk of heterogeneity, both DNA-based analysis and electron microscopy on chorionic villi are recommended for prenatal examination for juvenile neuronal ceroid lipofuscinosis.

Child↗
PubMed1989

Lysosomal storage of the DCCD reactive proteolipid subunit of mitochondrial ATP synthase in human and ovine ceroid lipofuscinoses.

The ceroid lipofuscinoses (Batten's disease) are a group of neuro-degenerative lysosomal storage diseases of children and animals that are recessively inherited. In the diseased individuals fluorescent storage bodies accumulate in a wide variety of cells, including neurons. The material stored in the cells of sheep affected with ceroid lipofuscinosis is two-thirds protein. The stored material does not arise from lipid peroxidation or a defect in lipid metabolism, and the lipid content is consistent with a lysosomal origin for the storage bodies. The major protein stains poorly with Coomassie blue dye and is soluble in organic solvents. It has an apparent molecular weight of 3,500 and its amino acids sequence is identical to that of the dicyclohexylcarbodiimide (DCCD) reactive proteolipid, subunit c, of mammalian mitochondrial ATP synthases. Apart from removal of mitochondrial import sequences, it has not been modified post-translationally. At least 50% of the mass of the storage bodies is composed of this protein. A minor protein sequence related to the 17-kDa subunit of vacuolar H(+)-ATPase is also found in storage bodies isolated from pancreas. As in humans and cattle, the ovine protein is the product of two expressed genes named P1 and P2. In normal and diseased animals there are no differences in sequences between P1 cDNAs or P2 cDNAs, nor do levels of mRNAs in liver for P1 or P2 differ substantially between normal and diseased animals. Both normal and diseased sheep also express a spliced pseudogene encoding amino acids 1 to 31 of the mitochondrial import presequence. The peptides they encode differ by one amino acid; arginine-23 is changed to glutamine in the diseased sheep. Storage bodies isolated from brains and pancreas of children affected with the juvenile and late infantile forms of ceroid lipofuscinosis also contain large amounts of material that is identical to subunit c of ATP synthase. However, the protein is not present in storage bodies isolated from brains of patients affected with the infantile form of the disease, and these storage bodies contain other unidentified proteins. It is possible that the cause of ovine, juvenile and late infantile ceroid lipofuscinoses is related to a defect in degradation of the subunit c of mitochondrial ATP synthase.

Amino Acid Sequence↗
PubMed1991

Bovine ceroid-lipofuscinosis (Batten's disease): the major component stored is the DCCD-reactive proteolipid, subunit C, of mitochondrial ATP synthase.

The ceroid-lipofuscinoses (Batten's disease) are a group of recessively inherited lysosomal storage diseases of children and animals in which there is intracellular accumulation of a fluorescent lipopigment in a wide variety of cells. Lipopigment bodies isolated from pancreas, liver, kidney and brain tissue from a heifer affected with ceroid-lipofuscinosis contained between 55 and 62% protein. A dominant component comigrated on LDS-PAGE with the major low molecular weight protein stored in ovine ceroid-lipofuscinosis. It was identified by amino acid sequence and mass spectroscopy as the full subunit c of mitochondrial ATP synthase, normally found only in the inner mitochondrial membrane, where it is estimated to account for 2-4% of the membrane protein. In pancreatic lipopigment it accounted for at least 40% of the total lipopigment mass and this storage was considered specific to the disease. No other mitochondrial proteins were found in storage bodies. These results are similar to those found in studies on the ovine and the late infantile and juvenile human forms of the disease. It is concluded that bovine ceroid-lipofuscinosis is also a proteolipid proteinosis in which subunit c of mitochondrial ATP synthase is specifically stored in lysosome derived organelles.

Amino Acid Sequence↗
PubMed1991

Primary extracellular ceroid type lipopigment. A histochemical and ultrastructural study.

An extracellular ceroid-type (ECC) lipopigment which appears histologically as wavy hyaline membranes or, less frequently, as an amorphous solid or broadly reticulated mass is described. Its ultrastructure is either amorphous or membranous and consists either of simple linear membrane-like aggregates or elaborated trilaminar membranes. The histochemical profile is, as in histiocytic intracellular ceroid, dominated by autofluorescence, strong hydrophobicity, acid and extraction resistance. Staining for aromatic acid residues and periodic acid-Schiff positivity are strong but variable. Lectin receptors are either absent or sparse. The pigment is found solely within the lipid rich tissue debris, bound to processes marked by necrosis of adipose or steatosed tissues and interpreted as originating de novo extracellularly from liquid unsaturated lipids under the influence of local enzymatic and nonenzymatic lipid oxidation catalysts. A hitherto unknown form of extracellular ceroid is the so-called membranocystic lesion found in Nasu-Hakola's disease, in several other conditions and in annular ceroid in human atheromas.

Adipose Tissue↗
PubMed1979

Hermansky-Pudlak syndrome. Pulmonary manifestations of a ceroid storage disorder.

The Hermansky-Pudlak syndrome is a form of oculocutaneous albinism, characterized by a qualitative platelet defect and deposition of ceroid-like material throughout the reticuloendothelial system. During a 16 month period five patients with Hermansky-Pudlak syndrome presented with symptoms, chest films and pulmonary function studies consistent with restrictive pulmonary disease. In two patients, lung biopsies revealed diffuse interstitial fibrosis. However, light and electron microscopy demonstrated ceroid-like material within alveolar macrophages. In addition, two patients presented with inflammatory bowel disease with deposition of ceroid-like material in the colon. This disorder appears to be more common than is currently recognized and should be considered in the differential diagnosis of diffuse interstitial pulmonary disease and inflammatory bowel disease. A relationship between the deposition of ceroid-like material and pulmonary fibrosis is discussed in light of recent research concerning inflammatory processes. In view of the serious pulmonary, gastrointestinal and hematologic consequences of this syndrome, there is a need for genetic counseling of these patients.

Adult↗
PubMed1986

Oxidized low density lipoprotein induces ceroid accumulation by murine peritoneal macrophages in vitro.

The presence of ceroid pigment inclusions within macrophage foam cells is a well-recognized phenomenon in human atherosclerosis but its significance is unclear. Murine peritoneal macrophages, maintained in a medium containing 10% lipoprotein-deficient fetal calf serum to which oxidized low density lipoprotein (LDL) has been added, rapidly accumulate similar ceroid inclusions. However, cells exposed to LDL, acetyl--LDL or dextran sulphate--LDL complexes fail to develop ceroid under the same culture conditions. Oxidation of LDL results in considerable physico-chemical changes to both protein and lipid moieties, and these may be important in the uptake of the particles by macrophages and, subsequently, the accumulation of intracellular ceroid.

Animals↗
PubMed1987

Magnetic resonance imaging in neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinosis is a group of neurodegenerative disorders characterized by accumulation of lipofuscin and/or ceroid within the tissues of the body. These entities are manifest by visual, intellectual, and motor deterioration as well as recurrent seizures. Computed tomography has been shown to demonstrate changes of cerebral atrophy in more severely affected patients. Seven patients with neuronal ceroid lipofuscinosis were examined with both computed tomography and magnetic resonance imaging, and the results were correlated with the clinical severity of the disorder. Two less severely affected patients had normal results on computed tomography and magnetic resonance imaging studies. Varying degrees of cerebral atrophy were seen in the remaining five patients with both computed tomography and magnetic resonance imaging. Severity of atrophy correlated with the severity of disability in these patients. Abnormal white matter was seen in the two most severely affected patients only with magnetic resonance imaging. Although the findings in patients with neuronal ceroid lipofuscinosis were nonspecific, the increased sensitivity of magnetic resonance imaging for subtle white matter abnormalities over computed tomography may prove helpful in monitoring the progression of this rare disorder.

Adolescent↗
PubMed1992

Oxidized LDL ceroid, and prostaglandin metabolism in human atherosclerosis.

A noted histological feature of human atherosclerotic lesions upon dissection is the presence of a 'pigment' referred to as ceroid; however the significance of ceroid in human fatty streaks and atherosclerotic plaques is not certain. The research focus to this point has presumed that ceroid synthesis and intracellular accumulation is harmful and may have adverse effects on lesion progression or reversibility. Alternatively, ceroid production may be a defense mechanism employed by cells in the artery wall to prevent uncontrolled synthesis and release of prostaglandins (PGs) or prostaglandin-precursors locally. Export of PGs or PG precursors may promote blood platelet aggregation at the site of export. A feedback inhibition mechanism will arrest the cellular export of prostaglandins, thus ending a potentially disastrous premature clotting event.

Arteriosclerosis↗
PubMed1996

Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores.

Serious studies of the formation mechanisms of age-related pigments and their possible cellular influence have been hampered for a long time by discrepancies and controversies over the definition, fluorescence emission, origin, and composition of these pigments. This review discusses several critical controversies in this field and lay special emphasis on the cellular and biochemical reactions related to the formation mechanisms of lipofuscin, ceroid, advanced glycation end-products (AGEs), and age pigment like fluorophores (APFs). Various amino compounds and their reaction with secondary aldehydic products of oxygen free radical-induced oxidation, particularly lipid peroxidation, are important sources of the fluorophores of ceroid/lipofuscin, which progressively accumulate as a result of phagocytosis and autophagocytosis of modified biomaterials within secondary lysosomes of postmitotic and other cells. Lipofuscin is the classical age pigment of postmitotic cells, while ceroid accumulates due to pathologic and experimental processes. There are good reasons to consider both ceroid and lipofuscin as materials of the same principal origin. The age-related intracellular fluorophores of retinal pigment epithelium (RPE) seems to represent a special class of lipofuscin, which partly contains derivatives of retinoids and carotenoids. Saccharide-originated fluorophores, principally AGEs formed during glycation/Maillard reactions, may be mainly responsible for the extracellular fluorescence of long-lived proteins, such as collagen, elastin, and lens crystalline. Although lipofuscin, ceroid, AGEs, and APFs can be produced from different types of biological materials due to different side reactions of essential biology, the crosslinking of carbonyl-amino compounds is recognized as a common process during their formation.

Aging↗
PubMed1998

Colocalization of iron and ceroid in human atherosclerotic lesions.

The presence of ceroid, a complex of protein associated with oxidized lipids, is commonly observed in human atherosclerotic lesions. When the human aortic walls were examined by Perls' staining, it was found that the iron deposits were evident in aortas with atherosclerosis. The extent of iron deposition was associated with the severity of the lesion. Furthermore, the iron deposits appeared to be colocalized with ceroids either extracellularly or intracellularly in foam cell-like macrophages or smooth muscle cells. Electron microscopy and X-ray microanalysis revealed that some of the extracellular iron aggregates were present within the ceroids. Likewise, some of the subcellular iron aggregates were found to be located near the lipid droplets or within the ceroids of foam cells. Collectively, these observations support the theory that the lipid oxidation occurring in lipid-laden cells of aortic lesions is facilitated by iron-overload in these cells.

Adult↗