Larry Schneck

Spongy degeneration of the central nervous system (van Bogaert and Bertrand type; Canavan's disease). A review.

Abstract The clinical, genetic, morphological, and biochemical aspects of spongydegeneration of the central nervous system in infancy, including our own seven cases, are reviewed. Although the pathogenesis is still obscure, recent ultrastructural and biochemical studies have demonstrated unique features that are consistent, with the accumulation of excessive fluid mainly within the astrocytic cytoplasm and myelin lamellae. The primary cause of fluid aggregation is unknown. However, ultrastructural and histochemical studies suggested that spongy degeneration is primarily due to a metabolic disturbance of abnormal astrocytic mitochondria. Further studies of these organelles therefore may provide a better understanding of this disease.

PRENATAL DIAGNOSIS OF TAY-SACHS DISEASE

Abstract Uncultured cells and fluid collected by amniocentesis during the second trimester from a mother of a child with Tay-Sachs disease were shown to have trace amounts of hexosaminidase-A activity. Accordingly the pregnancy was terminated. Biochemical and morphological studies of the aborted fetal tissue confirmed the prenatal diagnosis of Tay-Sachs disease.

Ophthalmoplegia plus with morphological and chemical studies of cerebellar and muscle tissue

Abstract A case resembling the syndrome of “ophthalmoplegia plus” is reported. Chemical and morphological studies on biopsied tissue from the cerebellum, ocular, and somatic muscle revealed abnormal mitochondria in all three tissues. There were no abnormalities in cerebellar lipids. While this case is clinically similar to cases of ophthalmoplegia plus and has mitochondrial changes similar to oculocraniosomatic neuromuscular disease with “ragged-red” fibers, no “ragged-red” fibers or lipid accumulations were observed in any of the muscle tissue examined. Ophthalmoplegia plus may be a neurogenic rather than myopathic disorder with associated mitochondrial dysfunction.

Biochemical and Clinical Aspects

Lipids, with certain notable exceptions, may be operationally defined as organic-solvent-soluble, water-insoluble compounds. The three major classes of lipids in the central nervous system are cholesterol, glycerophospholipids, and sphingolipids. Sphingosines are 1,3-dihydroxy-2-amino-hydrocarbons that form a series of lipids by substitution on both the 1-hydroxyl and the amino groups. At present, more than 30 sphingosines and their hydroxy derivatives (phytosphingosines) have been recorded from natural lipids. The amino group of sphingosine is usually acylated with a long-chain (C14–C26) fatty acid. This amide, N-acylsphingosine, is generically known as ceramide. It is the backbone for the synthesis of sphingolipids. The different sphingolipids are formed when the terminal hydroxy group of ceramide is substituted with various compounds. In sphingomyelin, the primary hydroxy group of sphingosine is esterified with choline phosphate. The glycosphingolipids are sphingolipids with a sugar moiety attached through β-glycosidic linkage to the corresponding ceramide. Cerebroside is the generic term for a group of ceramide monohexosides. Ceramide glucose is known as glucocerebroside and ceramide galactose as galactocerebroside. The latter monohexoside is the major cerebroside in normal adult brain. Sulfatides are sulfuric acid esters of cerebrosides with the sulfate at the carbon atom 3 of the galactose moiety. Complex glycosphingolipids are ceramide glycosides containing more than one monosaccharide unit and are known as ceramide oligosaccharides. A ceramide dihexoside contains two sugar moieties; ceramide trihexoside, three sugars; ceramide tetrahexoside, four sugars; etc. The ceramide oligosaccharides may be partitioned into the neutral glycolipids and the gangliosides. The carbohydrate residues of the neutral glycolipids are important in various immunochemical reactions.1–3

Fine Structure of Spongy Degeneration of the Central Nervous System (van Bogaert and Bertrand Type)

The present study describes the fine structure of cortex and white matter of a one year old Jewish boy afflicted with spongy degeneration of the brain. The most characteristic clinical and pathologic feature of this disease is megalencephaly which is due to increased intracellular water content in the brain, mainly in the subcortical white matter. The light microscopic picture was similar to that previously reported. Electron microscopically, multiple vacuoles in the subcortical white matter and deep cortical lamina (fusiform layer) were due to separation of the lamellae of myelin. The vacuoles were present between the major dense lines of the myelin membranes, and it is conjectured that the obscured intraperiod lines might be the origin of these vacuoles. The extracellular spaces in the subcortical white matter were widened due to the rupture of the myelin lamellae and astrocytic cell membranes. It is hypothesized that a secondarily increased extracellular water content in the white matter might have accelerated further degeneration in the white matter at the advanced stage. There were smaller vacuoles present in the cortex, especially in the ganglionic layer which were the result of marked enlargement of astrocytes and their processes, although no increased extracellular spaces or ruptured cell membranes were present. The large and pale astrocytic nuclei described as Alzheimer type II by light microscopy appeared ultramicroscopically also enlarged and were seen to contain sparse nucleoplasmic granules, loss of chromatin and distinct nucleoli with preserved nucleolonema. Marked changes in size, and frequently in appearance, of mitochondria were observed in the processes of the astrocytes in the cortex, especially in the ganglionic layer. Histochemical studies showed that the activity of ATPase within these mitochondria was decreased when compared with that of normal brain tissue. The fine structure of the neurons, oligodendroglia and blood vessels was not altered.

Identification of Tay-Sachs disease carriers by acrylamide gel electrophoresis.

Abstract 1. 1. For carrier detection in the general population, a simple, rapid quantitative acrylamide gel electrophoretic technique has been developed which employs a fluorogenic (umbelliferyl) substrate and automatic fluorimetric scanning of the gels. 2. 2. With the procedure the leukocytes of 6 Tay-Sachs disease carriers had a range of N-acetylhexosaminidase A values of 33–52% (mean = 49% A) while the normal range was 62–76% (mean = 66% A) with no overlap between the two groups. 3. 3. The presence of two isoenzymes, A and B, of N- acetyl -β- d - hexosaminidase (β-2-acetamido-2-deoxy- d -acetamidodeoxyglucohydrolase, EC 3.2.1.30) in the leukocytes of normal individuals (66% A/34% B) and absence of the A form in leukocytes of 12 Tay-Sachs disease patients has been confirmed.

Fine Structural Localization of Two Hydrolytic Enzymes in the Cerebellum of Children with Lipidoses

The fine structural localization of acid phosphatase (AcPase) and thiolacetate esterase activities were studied in biopsy tissue from the cerebellums of 2 children with Tay-Sachs disease (TSD), one child with late infantile amaurotie idiocy (LIAI), and one child with an acid mucopolysaccharidosis related to Hurlers disease (All). Localization of esterase was also studied in cerebellar tissue from a child with Niemann-Picks disease (NPD). In all cases AcPase and organophosphorus resistant esterase activities were localized largely in the abnormal lipid cytosomes characteristic of each disease. It is concluded that these lipid structures, which bear an apparent relationship to the endoplasinic reticulum, are lysosomes of the digestive or residual body type.

Congenital failure of myelinization: Pelizaeus‐Merzbacher disease?

MERZBACHER disease was restricted to a unique and characteristic combination of clinical and pathological criteria.182 Merzbacher conceived the disorder to be the result of a congenital aplasia of myelin sheaths.2 The original criteria have been gradually expanded and modified to accommodate an ever-increasing number of cases, and consequently the eponymic designation has lost much ef its original clinical value.3 The nosologic cohfusion has been compounded by speculative concepts of pathogenesis.3-7 The present case offers biochemical and morphological support for the concept of congenital arrest or aplasia of myelin sheaths. Furthermore, there is circumstantial evidence relating this case to Pelizaeus-Merzbacher disease, and thus the pathogenesis of PelizaeusMerzbacher disease may be associated with a failure of myelination.

Electron microscopic and enzyme histochemical studies of cerebellum, ocular and skeletal muscles in chronic progressive ophthalmoplegia with cerebellar ataxia

SummaryElectron microscopic and enzyme histochemical studies were performed on the cerebellum and the ocular and deltoid muscles from a 38 year old woman who developed bilateral ptosis at the age of nine years. Histologically the cerebellum appeared normal. The biopsies of three ocular muscles showed varying sizes of muscle fibers which were rounded and contained increased numbers of subsarcolemmal nuclei. The deltoid muscle stained by hematoxylin and eosin appeared normal, but the trichrome stain showed increased numbers of red granules within the sarcolemma corresponding ultrastructurally to increased numbers of abnormal mitochondria. These abnormal mitochondria displayed increased reaction products with LDH, NADH and SDH preparations, while the muscle gave normal reaction in phosphorylase, PAS and myosin ATP preparations. Chemical studies on the cerebellum showed normal proteolipids, glycolipids and phospholipids. Ultrastructurally, the cerebellum, the myofibers of three ocular muscles and the deltoid muscle exhibited abnormal mitochondria which showed peculiarly arranged circular cristae. They frequently contained paracrystalline structures which consisted of individual tubules arranged in a helical pattern. Frequently, the abnormal mitochondria were replaced by dense rectangular inclusions and occasionally showed complete transition to crystalline structures.

Electron miscroscopic and enzyme histochemical studies of the cerebellum in spongy degeneration

SummaryElectron microscopic and enzyme histochemical studies were performed on the cerebellum from a 9 month old Jewish boy with spongy degeneration. Histologically, the main pathological changes were noted in the Purkinje cell layer, the deeper areas of the granular cell layers and the subcortical white matter. Ultrastructurally, multiple vacuoles were present within the swollen cytoplasm and processes of protoplasmic astrocytes in the cortex, while in the subcortical white matter vacuoles were observed within splitting myelin lamellae as well as within astrocytes. There were also abnormal mitochondria within swollen protoplasmic astrocytic cytoplasm and processes which in ATPase preparations showed little or no reaction product. However, the fibrillary astrocytes were not swollen and contained intact mitochondria which showed normal reaction product in ATPase preparations. Since the myelin changes are known to be nonspecific and secondary to abnormal fluid accumulation, the characteristic distribution of the multiple vacuoles in the central nervous system in this disorder seems primarily to be related to swelling of the protoplasmic astrocytes.