Ichthyosis and neutral lipid storage disease

A boy with a lipid storage disease characterized by lamellar ichthyosis, cataracts, hepatosplenomegaly, and leukocyte vacuoles has been identified in a Sicilian family. This patient shows all the characteristics of ichthyosis and neutral lipid storage disease (Chanarin-Dorfman syndrome). Family data confirm an autosomal recessive inheritance; the heterozygotes may be detected by the presence of vacuoles in circulating eosinophils.     

Morphological features in a neutral lipid storage disease.

The morphological changes in a patient with a generalized storage disease characterized by the intracellular deposition of neutral lipid are described. There is widespread accumulation of lipid in the cytoplasm of many cells and in occasional nuclei. Diagnosis may be facilitated by the recognition of clear vacuoles in the cytoplasm of granulocytes in blood films. In jejunal biopsies vacuolation of the epithelial cells may simulate the appearances of a-betalipoproteinaemia. The lipid inclusions consist largely of normal triglycerides and are free in the cytoplasm, unassociated with any organelle. The biochemical basis of the lesions is uncertain. Although there are lipoprotein abnormalities the primary defect appears to be intrinsic to the cell and may involve either a defective cytoplasmic lipase or an impaired uptake and utilization of fatty acids by mitochondria.     

Dorfman-Chanarin syndrome: a rare neutral lipid storage disease

Dorfman-Chanarin syndrome is a rare neutral lipid storage disorder characterized by ichthyosis, lipid vacuolations in peripheral leucocytes, and multisystem involvement. It is an autosomal recessive disorder caused by mutations in the CGI-58 gene. A total of 42 cases have been reported worldwide till February 2009 out of which 4 have been previously reported from India. We report a case of a 20-month-old male with congenital ichthyosis, organomegaly, and bilateral cryptorchidism. Examination of the peripheral smear revealed lipid vacuoles in the leucocytes consistent with Jordan's anomaly, which was confirmed by transmission electron microscopy. Liver biopsy revealed micronodular cirrhosis with macrovesicular steatosis while skin biopsy showed ichthyosis vulgaris. Dorfman-Chanarin syndrome was diagnosed on the basis of clinical and laboratory criteria with certain unreported manifestations. Dietary modifications were instituted and followed up after 1 year with promising results. This emphasizes the importance of neonatal screening for lipid vacuolations in peripheral blood in all cases of congenital ichthyosis.     

Tangier disease: one explanation of lipid storage.

Normal high-density lipoproteins are absent from plasma in Tangier disease, and the disorder is characterized by accumulation of cholesteryl esters in several tissues, particularly those of the reticuloendothelial system. Electron microscopy of the abnormal high-density lipoproteins in the plasma of three patients with Tangier diseases revealed large (68-nm), flattened, translucent particles in all cases. These particles were most abundant in the plasma of the splenectomized patient. Restriction of dietary fat eliminated or drastically reduced the numbers of these particles among the Tangier high-density lipoproteins. Thus abnormal products of chylomicron metabolism that appear to occur in plasma in this disorder may be targets for phagocytosis and may be at least one source of the cholesteryl esters that accumulate in reticuloendothelial tissues in Tangier disease.     

Lipid storage disease: Part II. Ultrastructural pathology of lipid storage cells in sphingolipidoses

The ultrastructural pathology of the stored materials in lipid storage cells, particularly of macrophagic nature, in various disorders of sphingolipidosis was investigated. Cell morphology of the lipid storage cells was largely divided into two groups; one had peculiar cell morphology, such as Gaucher cells or globoid cells, and the other showed the appearance of foam cells. These cytological characteristics of the lipid storage cells were closely related to the ultrastructural configuration of lipid storage inclusions. By transmission electron microscopy, the fundamental structures of the stored materials were classified into two types; tubular and lamellar. The tubular structures were formed by accumulation of ceramide or monohexosyl ceramide, whereas the lamellar structures were formed by accumulation of larger sphingolipids than monohexosyl ceramide. These tubular structures were proven to consist of multilayers of lamellae, which are considered fundamentally similar to the lamellar structures. Almost all the lipid storage inclusions are considered to be of lysosomal origin, because of their encirclement by a single unit membrane and localization of acid phosphatase activity, and participation of heterophagic or autophagic mechanisms as for the development of the inclusions may be noted. Besides, the occurrence of secondary lipid storage was pointed out in some disorders of sphingolipidosis.     

Gaucher's disease: a case history with extensive lipid storage in the brain

Patients with acute infantile or type II neuropathic Gaucher's disease demonstrate neurologic deficits that are seemingly greater than the extent of the central nervous system involvement found at autopsy. Examination of the brain of an affected child shows widespread deposition of lipid in a pattern not recognized heretofore. Based on these observations, the authors hypothesize that widespread deposition of the Gaucher glucocerebroside elicits a mild tissue response, which functionally becomes highly significant.     

Rab proteins implicated in lipid storage and mobilization

Abnormal intracellular accumulation or transport of lipids contributes greatly to the pathogenesis of human diseases. In the liver, excess accumulation of triacylglycerol (TG) leads to fatty liver disease encompassing steatosis, steatohepatitis and fibrosis. This places individuals at risk of developing cirrhosis, hepatocellular carcinoma or hepatic decompensation and also contributes to the emergence of insulin resistance and dyslipidemias affecting many other organs. Excessive accumulation of TG in adipose tissue contributes to insulin resistance as well as to the release of cytokines attracting leucocytes leading to a pro-inflammatory state. Pathological accumulation of cholesteryl ester (CE) in macrophages in the arterial wall is the progenitor of atherosclerotic plaques and heart disease. Overconsumption of dietary fat, cholesterol and carbohydrates explains why these diseases are on the increase yet offers few clues for how to prevent or treat individuals. Dietary regimes have proven futile and barring surgery, no realistic alternatives are at hand as effective drugs are few and not without side effects. Overweight and obesity-related diseases are no longer restricted to the developed world and as such, constitute a global problem. Development of new drugs and treatment strategies are a priority yet requires as a first step, elucidation of the molecular pathophysiology underlying each associated disease state. The lipid droplet (LD), an up to now overlooked intracellular organelle, appears at the heart of each pathophysiology linking key regulatory and metabolic processes as well as constituting the site of storage of both TGs and CEs. As the molecular machinery and mechanisms of LDs of each cell type are being elucidated, regulatory proteins used to control various cellular processes are emerging. Of these and the subject of this review, small GTPases belonging to the Rab protein family appear as important molecular switches used in the regulation of the intracellular trafficking and storage of lipids.     

Ein Fall von Ichthyosis cornea

Ohne Zusammenfassung     

组织化学和免疫组织化学技术对脂质沉积性肌病和糖原沉积性肌病的鉴别

目的脂质沉积性肌病和糖原沉积性肌病是罕见的肌肉疾病,其常规病理形态十分相似。本文探讨这两种疾病组织化学和免疫组化反应,寻找其鉴别诊断的形态差异。方法采用三磷酸腺苷(ATP)酶、还原性尼克酰胺腺嘌呤二核苷酸(NADH-Tr)、苏丹Ⅲ、PAS组织化学染色和抗肌萎缩蛋白(Dystrophin)免疫组化染色,分析2例脂质沉积性肌病和2例糖原沉积性肌病的组织形态特征和差别。结果脂质沉积性肌病和糖原沉积性肌病在常规HE染色均表现为肌纤维内出现大量的空泡,但前者空泡大小较一致,且边界清楚,后者空泡大小差异大,边界不清。ATP酶组化染色显示脂质沉积性肌病出现空泡变性的肌纤维均为Ⅰ型肌纤维,而糖原沉积性肌病出现空泡变性的肌纤维两型均有,以Ⅰ型严重。脂肪染色和糖原染色可作为这两种肌病的确诊依据。Dystrophin免疫组化染色显示脂质沉积性肌病的肌纤维强阳性,而在糖原沉积性肌病的反应为不连续弱阳性。结论组化和免疫组化检测可用于脂质沉积性肌病和糖原沉积性肌病的鉴别诊断。     

Ryanodine receptor antagonists adapt NPC1 proteostasis to ameliorate lipid storage in Niemann-Pick type C disease fibroblasts

Niemann-Pick type C disease is a lysosomal storage disorder most often caused by loss-of-function mutations in the NPC1 gene. The encoded multipass transmembrane protein is required for cholesterol efflux from late endosomes and lysosomes. Numerous missense mutations in the NPC1 gene cause disease, including the prevalent I1061T mutation that leads to protein misfolding and degradation. Here, we sought to modulate the cellular proteostasis machinery to achieve functional recovery in primary patient fibroblasts. We demonstrate that targeting endoplasmic reticulum (ER) calcium levels using ryanodine receptor (RyR) antagonists increased steady-state levels of the NPC1 I1061T protein. These compounds also promoted trafficking of mutant NPC1 to late endosomes and lysosomes and rescued the aberrant storage of cholesterol and sphingolipids that is characteristic of disease. Similar rescue was obtained using three distinct RyR antagonists in cells with missense alleles, but not with null alleles, or by over-expressing calnexin, a calcium-dependent ER chaperone. Our work highlights the utility of proteostasis regulators to remodel the protein-folding environment in the ER to recover function in the setting of disease-causing missense alleles.     

Lysosome lipid storage disorder in NCTR-BALB/c mice. I. Description of the disease and genetics.

We describe a strain of BALB/c mice, designated NCTR-BALB/c, carrying a new genetic disorder characterized by excessive tissue deposition of cholesterol and phospholipid. The mice exhibit progressive incoordination, grow less rapidly, and die 80-120 days after birth. In comparison with control animals of the same age, organ weights in the affected animals are lower in absolute value but higher relative to body weight, except for the thymus, which is atrophied, and for the lung and testes, whose absolute weights are not changed. Vacuolated cells are found in many tissues, and large foam cells are present in reticuloendothelial system (RES)-rich organs. Compared with those of BALB/c controls, serum lipoproteins migrate more slowly on electrophoresis; the amount of beta-lipoproteins is increased, while alpha-lipoprotein content is decreased. Serum total cholesterol remains normal. The serum activities of aspartate aminotransferase, creatine phosphokinase, and N-acetyl-beta-glucosaminidase are elevated. Free cholesterol levels are increased 8-10-fold in liver, spleen, and thymus, and about 2-fold in other tissues; but esterified cholesterol levels are normal. The phospholipid content of several tissues is increased 50-100%, largely as a result of an increase in sphingomyelin content. Significant increases in phosphatidylcholine occur also in spleen and lung. The disorder is inherited, affecting both sexes equally, and appears to be transmitted as an autosomal recessive mutation.     

Fatal lipid storage myopathy with deficiency of cytochrome-c-oxidase and carnitine

Summary Two newborn female siblings fell ill with apathy, failure of suckling and a generalized progressive muscular hypotonia. Death occured at the age of 7 weeks, obviously caused by impairment of respiratory musculature. Biochemical studies in one child revealed carnitine deficiency especially in skeletal muscle; hepatic encephalopathy was absent. Both children had a generalized hyperaminoaciduria, an unusual finding in primary carnitine deficiency.Besides fatty metamorphosis of the liver, bilateral hydroureters and tubular calcifications of both kidneys, morphological studies showed a generalized lipid storage myopathy which predominated in Type-I-fibres and was accentuated in the muscles of the neck. Enzymehistochemical electron microscopy in longterm frozen muscle demonstrated that cytochrome-c-oxidase activity was absent not only in myopathic but also in most of the morphological unchanged muscle fibres. Only some fibres and endothelial cells displayed normal activity of mitochondria. Biochemically no cytochrome aa₃ (cytochrome-c-oxidase) could be found in skeletal muscle; cytochrome b was almost undetectable. - In newborns with fatal lipid storage myopathy and carnitine deficiency it seems necessary to look for additional defects in the respiratory chain. Enzyme histochemical electron microscopy is a sensitive method in identifying cytochrome-c-oxidase even after a 12 months period of storage.     

Increased intramuscular lipid storage in the insulin-resistant and endurance-trained state

Numerous studies have reported a strong correlation between intramuscular triacylglycerol (IMTG) content and insulin resistance. However, the proposed relationship between IMTG accumulation and skeletal muscle insulin resistance is not unambiguous, as trained athletes have been shown to be markedly insulin sensitive despite an elevated IMTG storage. Though the latter has often been attributed to differences in muscle fibre type composition and/or structural characteristics of the intramyocellular lipid deposits, recent studies have failed to provide such evidence. The greater insulin sensitivity despite an elevated IMTG deposition in the endurance-trained state has often been described as a metabolic paradox. However, divergent metabolic events are responsible for the greater IMTG content in the endurance-trained versus insulin-resistant states. The greater IMTG storage in the trained athlete represents an adaptive response to endurance training, allowing a greater contribution of the IMTG pool as a substrate source during exercise. In contrast, elevated IMTG stores in the obese and/or type 2 diabetes patient seem to be secondary to a structural imbalance between plasma free fatty acid availability, fatty acid (FA) storage and oxidation. Therefore, the reported correlation between IMTG content and insulin resistance does not represent a functional relationship, as it is strongly influenced by training status and/or habitual physical activity. It can be argued that the ratio between IMTG content and muscle oxidative capacity represents a more accurate marker of insulin resistance. Interventions to augment mitochondrial density and/or function are likely to improve the balance between FA uptake and oxidation and should be applied to prevent and/or treat insulin resistance.     

Pancreatic cancer and fibrinogen storage disease

BACKGROUND: Ductal adenocarcinoma is the most common type of pancreatic carcinoma while squamous, carcinosarcoma, sarcoma, giant cell carcinoma, and clear cell types are all rare. Hepatocellular fibrinogen storage disease is also an uncommon disorder which may be associated with hepatocellular carcinoma. Two cases of pancreatic carcinoma were encountered in a family with fibrinogen storage disease, further raising the possibility of a predilection to malignancy in this unusual disorder. The tumour in one case was of the rare clear cell type. These two cases are the basis for this report. METHODS: Sections were cut from retrieved paraffin embedded tissue and stained for routine histology. Immunohistochemistry using the avidin-biotin technique was applied for the expression of the markers p53 (D07), carcinoembryonic antigen (CEA), c-erbB-2, epithelial membrane antigen (EMA), and alpha-fetoprotein (AFP). RESULTS: Both cases were adenocarcinoma of pancreatic ductal origin. The tumour in one case showed features of a clear cell carcinoma. The tumour cells expressed p53, CEA, and EMA immunoreactivity and were negative for c-erbB-2 and AFP. CONCLUSIONS: Hepatocellular fibrinogen storage disease is rare and has been described in association with chronic hepatitis, cirrhosis, and rarely with hepatocellular carcinoma. This represents the first report of its association with carcinoma outside of the liver.