In silico modeling to predict drug-induced phospholipidosis.

Drug-induced phospholipidosis (DIPL) is a preclinical finding during pharmaceutical drug development that has implications on the course of drug development and regulatory safety review. A principal characteristic of drugs inducing DIPL is known to be a cationic amphiphilic structure. This provides evidence for a structure-based explanation and opportunity to analyze properties and structures of drugs with the histopathologic findings for DIPL. In previous work from the FDA, in silico quantitative structure-activity relationship (QSAR) modeling using machine learning approaches has shown promise with a large dataset of drugs but included unconfirmed data as well. In this study, we report the construction and validation of a battery of complementary in silico QSAR models using the FDA's updated database on phospholipidosis, new algorithms and predictive technologies, and in particular, we address high performance with a high-confidence dataset. The results of our modeling for DIPL include rigorous external validation tests showing 80-81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ≥80% leading to desired high negative and positive predictivity. These models are intended to be utilized for regulatory toxicology applied science needs in screening new drugs for DIPL.

[Metabolic myopathies - an overview]. / Metabolische Myopathien - ein Uberblick.

Metabolic disorders of energy production characterise the group of rare, mainly autosomal recessively inherited metabolic muscular diseases which are often associated with multi-systemic symptoms. In this report, an update on the clinics, pathophysiology, pathomorphology and current treatment options of metabolic myopathies will be given. Beyond classic phenotypes of these disorders, one should be aware of oligosymptomatic patients who can be easily missed. The relevant gene mutations and the pathophysiology and pathomorphology they cause are now known for almost all these metabolic diseases. Establishing the correct diagnosis has become even more important since highly specific therapy options are now available for at least some of these inherited disorders, e.g. enzyme replacement therapy in Pompe disease.

Lipidoses detected in Poland through 1993.

It is estimated that 70-100 children suffering from a lysosomal storage disease are born in Poland every year. From 1975 to 1993, the activity of various lysosomal enzymes was determined in the leukocytes, cultured skin fibroblasts, or hair roots from 5,594 patients, mainly children, in whom the diagnosis of a lipidosis was suspected. In that material 162 cases of a lipidosis were diagnosed. Metachromatic leukodystrophy seems to be the most frequent of the lipidoses; GM1 gangliosidosis is more frequent than GM2 gangliosidosis and Gaucher and Niemann-Pick diseases appear to be almost as frequent as the former.

Adult type of neuronal ceroid lipofuscinosis.

Adult neuronal ceroid lipofuscinosis (NCL), also called Kufs' disease, is clinically distinct from the other NCLs. It is a rare condition which is difficult to diagnose. More than 50% of the reported cases of Kufs' disease are not adult NCL and correspond very likely to a heterogeneous spectrum of lipidoses. Various clinical and genetic phenotypes of adult NCL may be recognized, one featuring a progressive myoclonus epilepsy. It is important to stress that in contradistinction with the juvenile and protracted juvenile NCL, there is no pigmentary degeneration of the retina. Adult NCL is an autosomal recessive condition but two families have an autosomal dominant inheritance. The diagnosis of adult NCL may be suggested by a careful evaluation of skin, rectal or brain biopsies with the electron microscope but the diagnosis is fraught with many hazards. The pathogenetic defect lies probably in the intracellular processing of lysosomal and perhaps of Golgi membranes. The recent discovery of subunit c of mitochondrial adenosine triphosphate synthase in the stored cytosomes represents certainly an interesting prospect for future developments.

Diagnosis and treatment of typical and atypical forms of lipopigment storage disorders.

Lipopigment storage disorders are common lysosomal diseases of unknown etiology. Four classic types have been delineated on a clinical basis, focused on the age of onset, visual and retinal impairment, epilepsy and progressive loss of mental and motor abilities. Lipopigments with ultrastructural characteristics distinct from lipofuscin accumulate mostly in the nerve cells but in many other cell types as well. Excess dolichol can be demonstrated in tissues and urine, but no primary accumulating substrate has been identified. Many cases with atypical features or course cannot be currently classified. Medical treatment includes, in all types, prevention of aspiration pneumonia with fundoplication and gastrostomy and avoidance of carbamazepine. In Spielmeyer-Vogt, Vitamin E and appropriate mental and physical stimulation improve the patient's quality of life.

Neuronal ceroid lipofuscinosis. Diagnosis from peripheral blood smear.

Neuronal ceroid lipofuscinosis (NCL), or Batten-Vogt's disease, is a disorder of young children who manifest visual, neurologic, and mental problems. The ophthalmologist can provide helpful diagnostic information by examining the fundus and performing an electroretinogram. In addition, diagnostic markers can be identified by examining circulating lymphocytes from a peripheral blood specimen with light and electron microscopy.

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 junvenile type, 1 patient with the late infantile type), the ultrastructural spectrum of residual bodies in the central and peripheral nervous system presented curvilinear profiles in all cases and regions investigated and many more ultrastructural patterns 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-fingerpint 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.

Familial juvenile neuronal storage disease. New disease or variant of juvenile lipidosis?

Two patients had an illness characterized by a positive family history, juvenile onset, macular cherry-red spots, myoclonus, generalized convulsions, and cerebellar ataxia. Neither had dementia, gargoyle facies, bone or joint deformities, or visceromegaly. Vacuolated lymphocytes were not seen in the peripheral blood or bone marrow. Specimens from the rectum and vermiform appendix showed Sudan black B-, Sudan III-, and PAS-positive granules within the neurons of the myenteric plexus. On electron microscopic examination, lysosome-like bodies, membranous cytoplasmic bodies, pleomorphic lamellated bodies, dense bodies, and lipofuscin-like bodies in the neurons were seen, with a suggestion of morphological transitional forms among them. Sialoglycopeptides, especially sialic acid, were increased in the urine, but excretion of acid mucopolysaccharides was normal. Assays of lysosomal enzymes in leucocytes showed normal enzymatic activity. On the basis of the clinical, biochemical, and histological results, we suggest that these two cases and four similar cases reported in the literature be classified differently from the previously described lipidoses, although it is not known whether these cases represent a new entity or merely a clinical variant of juvenile lipidosis.

Atypical juvenile neurolipidosis. Ultrastructural study of a cerebral biopsy.

The description is given of a structural and ultrastructural aspect of a cerebral biopsy specimen collected from a 17-year-old patient, with very frequent convulsive seizures, dementia, motor aphasia and spastic tetraparesis. The disease started at the age of 9 years and evolved very slowly. The morphologic diagnosis was neurolopidosis, the ultrastructural one was atypical juvenile lipofuscinosis, the electron microscopic aspect being identical to that of another 3 cases published in the literature: highly polymorphous membranogranulovesicular cytosomes.

[Globoid cells leukodystrophy apropos of a case of Krabbe's disease]. / Leucodystrophie à cellules globoïdes. A propos d'une observation de la maladie de Krabbe

A case of Krabbe's leucodystrophy is reported after photon and delayed ultrastructural microscopic study. Cerebroside overload within the cerebral globoid cells was shown as well as in the interstitial histiocytic infiltration of the peripheral nerves. Reviewed with the published literature, the characteristics of the inclusions observed seem to be unspecific and, from a morphological standpoint, Krabbe's disease may be related to the gangliosidoses.

The clinical classification of ceroid-lipofuscinosis. A statistical approach.

A revision of 108 published cases from the last ten years has been made, of patients suffering ceroid-lipofuscinosis, which includes two cases studied in our department. The statistical analysis of the initial symptoms, the age of onset and the disease's duration, permits us to conclude that possibly there exists, within this syndrome, four different forms in accordance with the age of onset. Each one of them has a typical clinical pattern. Our classification was compared with previously existing ones.

The mucopolysaccharidoses and mucolipidoses.

The mucopolysaccharidoses and mucolipidoses are recessively inherited lysosomal storage diseases. Each of the disorders can now be specifically identified in cultured fibroblasts. As a group these disorders clinically present with a Hurler-like phenotype. Genetic heterogeneity and variable expression of the same enzyme deficiency require a combined clinical and laboratory approach to the diagnosis of these disorders. This feature is demonstrated by mucopolysaccharidosis I. This diagnosis refers to a specific deficiency of the lysosomal enzyme alpha-L-iduronidase. Further characterization requires clinical assessment to determine whether the final diagnosis is the Hurler syndrome, the Scheie syndrome or the Hurler-Scheie compound. Clinically each of these three disorders may be difficult to distinguish from other mucopolysaccharidoses or mucolipidoses. There is no specific treatment currently available for any of these disorders. However, a specific diagnosis should be established in each case to insure an accurate prognosis (some of these disorders are compatible with near normal life expectancy and normal intelligence), appropriate genetic counseling for the family and timely use of prenatal diagnosis by amniocentesis which is available for each of these disorders.

[Atypical juvenile neurolipidosis. Ultrastructural study of a cerebral biopsy]. / Neurolipidose juvénile atypique. Etude ultrastructurale d'une biopsie cérébrale

Electron-microscopic findings on a brain biopsy in a 9-year-old male affected by juvenile lipidosis are reported. Two types of neuronal cytosomes were discribed: lamellar concentric bodies, resembling membranous cytoplasmic bodies, and polymorphous complex bodies, unit membrane bound including various material, mostly resembling lipofuscin. The same storage was found in glial and endothelial cells. Neurochemical data failed to pin-point any specific abnormalities. The present case cannot be classified in the category of neuronal ceroid-lipofuscinosis but seems similar to certain reported cases of atypicalneurolipidosis.

Ceroid-lipofuscinosis (Batten disease). Fluorescein angiography, electrophysiology, histopathology, ultrastructure, and a review of amaurotic familial idiocy.

Three children with ceroid-lipofuscinosis and their mother wer investigated fluorescein angiographically and electrophysiologically after definitive diagnosis of the oldest child had been made from a brain biopsy specimen studied biochemically, histopathologically, and ultrastructurally. The diagnostic features of the two classes of familial amaurotic idiocy (the gangliosidoses and the ceroidlipofuscinoses) are reviewed with emphasis on the importance of the fundus picture and fluorescein angiographic study in differentiating the two classes of disease and in identifying affected siblings.