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A case is described of Niemann–Pick type C2 disease presenting an infantile pneumopathic phenotype known to occur in this recently established, second, minor complementation group of Niemann–Pick type C (NPC) disease. However, the pulmonary involvement was unique, being dominated, in addition to the usual storage macrophage infiltration of the alveolar and septal compartments, by irregular emphysema attributed to storage cell migration into the bronchiolar lumen. The latter modified considerably the X-ray findings and hindered the initial clinical diagnosis. Otherwise, the storage phenotype, including the range of stored lipids, storage distribution, and cell and organ pathology, was found to be identical to that in the whole Niemann–Pick type C disease group dominated by NPC1. The biochemical findings (cholesterol esterification level) corresponded to the classical biochemical phenotype. Emphysema should thus be considered as a variant of the pulmonary NPC2 storage process, governed most probably by an epigenetic mechanism responsible for storage macrophage migration into the bronchiolar compartment.

Abstract: A case of long-standing subclinical cholesteryl ester storage disease (CESD) manifesting as hyperlipoproteinaemia type IIb without any hepatomegaly is described. The patient underwent surgical vascular interventions because of accelerated atherosclerosis, which dominated his middle age. CESD was an incidental finding when a liver biopsy specimen was taken because liver malignancy was suspected; the patient’s condition proved to be due to a cholangiocarcinoma, which led to his death at the of age 52. The autopsy showed moderate-intensity storage in the set of cells characterized by constitutional high-level receptor-mediated LDL endocytosis (hepatocytes, adrenal cortical cells) and also revealed storage in the Leydig cells. The severity with which histiocytes were affected varied regionally, ranging from minimal detectable storage or none at all (gut, lymph nodes, spleen) to extreme lysosomal expansion by cholesteryl ester liquid crystals (bone marrow) or by ceroid (lung, testicular stroma), or by both (liver). The density of the histiocytic population did not correlate with the degree to which parenchymal cells were affected except in the testicular stroma, where it was prominent. The patient was a mixed heterozygote for the G934A and ΔC673-5 mutations.

Cholesteryl ester storage disease and Wolman disease are rare autosomal recessive lipoprotein-processing disorders caused by mutations in the gene encoding human lysosomal acid lipase. Thus far we have elucidated the genetic defects in 15 unrelated CESD patients. Seven were homozygotes for the prevalent hLAL exon 8 splice junction mutation which results in incomplete exon skipping, while eight probands were compound heterozygotes for E8SJM and a rare mutation on the second chromosome. In this report, we describe the molecular basis of CESD in three compound heterozygous subjects of Czech and Irish origin. RFLP and DNA sequence analysis revealed that they were heteroallelic for the common G(934)-->A substitution in exon 8 of the hLAL gene and a mutation which, if inherited on both alleles, would be expected to result in complete loss of enzyme activity and to cause Wolman disease. In patients A. M. and J. J., two nucleotide deletions in exons 7 and 10 were detected, involving a T at position 722, 723, or 724 and a G in a stretch of five guanosines at positions 1064;-1068 of the hLAL cDNA. Both mutations result in premature termination of protein translation at residues 219 and 336, respectively, and in the production of truncated, inactive enzymes. Subject D. H., in contrast, is a compound heterozygote for the Arg(44)-->Stop mutation previously described in a French CESD proband. Combined with data in the literature, our results demonstrate that compound heterozygosity for a mutation causing Wolman disease is common among cholesteryl ester storage disease patients.

Abstract:  In a case of infantile mucolipidosis type II (I-cell disease), storage was identified at autopsy in serous-type secretory cells in exocrine pancreas, in the tracheal and sublingual salivary glands and in the chief (zymogenic) cells of the gastric oxyntic glands, suggesting a systemic involvement of this type of secretory cells. The content of specific secretory granules was inversely proportional to the intensity of the storage process. The mucus-producing cells were not affected. The serous glandular system is a novel storage site in I-cell disease. Review of archival material in three further cases confirmed the findings.

Three males (aged 10 years, 3 years 9 months and 2 years 8 months) with profound sphingomyelinase deficiency are presented. The sphingomyelin storage in the liver biopsies attained 30-fold, 65-fold and 16-fold increases against controls, respectively. Levels of bis(monoacylglyceryl) phosphate were also increased. In two cases the bone marrow contained foam cells with liquid crystals of sphingomyelin. Besides the visceral involvement dominated by hepatosplenomegaly, all three cases showed discrete, so far stationary (8 years, 42 months and 28 months) neuropathic features and retinal lesions resembling the classical cherry-red spot. Electrophysiological examinations showed a variable reduction of peripheral nerve conduction velocity and prolongation of the latencies of somatosensory, visual and auditory evoked potentials. Ultrastructural examination of skin nerves showed a slight storage, mainly in Schwann cells. In some myelinated fibres there were pseudomyelinic ovoids. The cases therefore displayed features of both A and B types of sphingomyelinase deficiency and should be conventionally classified as intermediate. However, the very low levels ofin vivosphingomyelin hydrolysis (not exceeding 6%, against 30±10% in type B and 77±5% in controls) were clearly within the range of type A values (5±2%). Accordingly, we suggest that the cases may be biochemically classified as variants of type A disease.

ABSTRACT: A case of infantile GM2gangliosidosis with high residual/S-hexosaminidase A activity toward the synthetic substrate 4-methylumbelliferyl-2-acetamido-2- deoxy-/S-D-glucopyranoside was diagnosed prenatally. Extracts from cultured amniotic fluid cells of the fetus had a hexosaminidase A activity of 27% of total hexosaminidase but were almost completely unable to degrade [3H]ganglioside GM2(less than 0.5% of control values) when assayed in the presence of the natural activator protein. These results were confirmed by analyses of fetal muscle fibroblasts, liver, and brain. All tissues examined showed a profound deficiency of ganglioside GM2galactosaminidase despite hexosaminidase A levels in the heterozygote range. In brain tissue, ganglioside GM2content was elevated more than 4-fold. Hydrolysis of p-nitrophenyl glucosaminide-6- sulfate, a substrate specific for hexosaminidases A and S, by tissue extracts was also markedly reduced but the residual activities found (5% in liver, 12% in fibroblasts, and 16% in brain) were much higher than those with the physiological lipid substrate, ganglioside GM2.

Summary An extremely benign variant of cholesterol ester storage disease (CESD) was diagnosed in two female patients aged 43 and 56 years. In one of them the course was entirely subclinical until a stroke at the age of 47, most probably a complication of secondary hyperlipoproteinaemia. The diagnosis was made accidentally in vivo during extensive examination for concomitant monoclonal gammapathy. The other patient (aged 56), still displays a fairly stable course with minor dyspeptic symptoms. The clinical findings in both patients were confined to moderate well tolerated hepatomegaly, hyperlipoproteinaemia of IIb type and xanthelasmata. Acid lipase activity was markedly deficient in peripheral leukocytes and cultured fibroblasts. These cases represent a rare adult variant the existence of which should be borne in mind in the differential diagnosis of chronic liver disease in advanced age and of hyperlipoporteinaemic states. The diagnostic criteria for the routine clinicopathological steps are summarized with emphasis on a special lipopigment deposition pattern, encompassing inhibition and modification of lipofuscin generation in hepatocytes and an excess of ceroid production in both portal and intralobular histiocytes. The varied ultrastructural appearance of the lysosomal limiting membrane complex is described.

Summary Fabry's disease was diagnosed in an adult patient as a lipid storage-induced non-obstructive hypertrophic cardiomyopathy. Stable angina pectoris started 15 years before death, was followed by slowly progressive heart failure and repeated pulmonary thromboembolism with death at 63 years. Autopsy disclosed enormous cardiomegaly (1100 g), cardiac storage of ceramide trihexoside (CTH) of the same intensity as in classical cases of generalized Fabry's disease (11 mg lipid/g wet weight) restricted to cardiocytes. Other tissues (liver, kidney, brain, pancreas, pulmonary artery, coronary arteries) were free of storage. Using proton magnetic resonance analysis on formaldehyde-fixed tissue the stored CTH was identified as globotriaosylceramide. It was enzymatically degradable by control cell cultures but left uncleaved by mutant reference Fabry cells. Alpha — galactosidase activities in peripheral leucocytes of all four of the patient's daughters were in the heterozygous range. The diagnostic difficulties in this monosymptomatic novel variant of Fabry's disease are stressed.

We describe here a male infant with a rare form of glycogenosis caused by deficiency of heart specific phosphorylase b kinase. The disease phenotype was characterized by severe glycogenosis restricted to the heart muscle with secondary rapidly progressive hypertrophic cardiomyopathy causing death at the age of 47 days.

We found two patterns of leptomeningeal storage that reflect two basic visceral storage patterns in Fabry disease. (i) A generalized-type leptomeningeal storage pattern, affecting all main leptomeningeal cell types (external arachnoideal epithelium, fibroblasts, vessel wall elements), was a consistent finding in three cases of classical generalized visceral phenotype. (ii) A localized leptomeningeal storage pattern was expressed, to a high degree, solely in the external arachnoidal epithelium; this pattern was found in one case with the variant visceral-restricted-type storage (confined to the cardiocytes). Thus, the external arachnoidal epithelium may be particurlarly susceptible to Fabry lipid storage, probably caused by a distinctly larger sustained lysosomal lipid load as compared to other cell types.

Summary: The histochemical examination of bioptic samples of the human skin revealed the strikingly high activity of an acid-a-D-mannosidase in Langerhans cells. This enzyme is highly soluble and its activity “in situ” can be demonstrated practically only with the semipermable membrane technic. The significance of this finding is briefly discussed.

Abstract: Immunohistochemical and biochemical studies of subunit c of mitochondrial ATP synthase (SCMAS) storage were carried out in neuronal ceroid lipofuscinosis (NCL) and in a series of unrelated inherited and acquired lysosomal disorders. In the NCL group, represented by the late infantile, early juvenile and juvenile types, SCMAS storage was generalized neurovisceral, with considerable difference in the visceral storage pattern between the types. In late infantile NCL the SCMAS storage was intensive and corresponded to the generalized, autofluorescent, uniformly curvilinear material, irrespective of the cell type affected. In both early juvenile and juvenile NCLs the SCMAS storage was strong and almost uniform in brain neurons, but did not correlate entirely with the visceral autofluorescent storage pool, being undetectable in autofluorescent storage deposits in a constant set of tissues. In the adult (Kufs) type, the brain neurons were stained with various intensity. In infantile NCL, SCMAS storage was restricted to some of the persisting neurons. In a series of inherited lysosomal enzymopathies and acquired lysosomal disorders, excessive SCMAS accumulation was found only in secondary neuronal lipopigments. It occurred as an early and more uniform phenomenon in mucopolysaccharidosis types I, II, IIIA and in polysulphatase deficiency, or as a delayed varied phenomeno in protracted variants of mucolipidosis I, Niemann-Pick types A and C, and GM2 and GM1 gangliosidoses. Neuronal ageing led to an irregular increase in immunodetectable SCMAS epitope in some neuronal lipofuscin granules. There was no evidence of significant SCMAS lysosomal accumulation in non-neural cells in the whole group, regardless of whether lipofuscin or ceroid accumulation occurred or not. The neuronal SCMAS storage is thus nosologically a common unspecific phenomenon, which is especially amplified in NCL. The specificity of the NCL storage process is shown by the fact that even lysosomes of non-neuronal cells in NCL accumulate SCMAS.