Anatole S. Dekaban

Medroxyprogesterone acetate in the treatment of seizures associated with menstruation

An 8-year-old girl who had a generalized seizure disorder from the age of 5 had an early onset of normal puberty and developed exacerbation of seizures and behavioral abnormalities during menstrual periods. The neurologic examination demonstrated only mild mental subnormality; a pneumoencephalogram showed slight ventricular dilatation. Oral medroxyprogesterone acetate (MPA) decreased seizure activity slightly. Subsequently following three biweekly injections of depot-MPA, the patients menses ceased, and she became seizure-free for 4 months. There was associated improvement in behavior and school performance. Serum gonadotropin values remained normal, and no side effects were observed, except for increased appetite and weight gain.

NEUROCHEMISTRY OF THE MUCOPOLYSACCHARIDOSES: BRAIN LIPIDS AND LYSOSOMAL ENZYMES IN PATIENTS WITH FOUR TYPES OF MUCOPOLYSACCHARIDOSIS AND IN NORMAL CONTROLS

Abstract— Lipids and certain lysosomal enzymes were measured in the cerebral gray and white matter and in the liver of unaffected controls and six patients with mucopolysaccharidosis (MPS). Three of the patients had MPS Type I (Hurler), one Type II (Hunter), one Type IIIA (Sanfilippo A) and one Type V (Scheie). The glycosaminoglycans (GAG) of those tissues have been fully characterized previously (Constantopouloset al., 1976).

Mucopolysaccharidosis Types IH, IS, II and IIIA: Glycosaminoglycans and Lipids of Isolated Brain Cells and Other Fractions from Autopsied Tissues

Abstract: Brain cellular fractions were prepared in bulk from four non‐neurological patients and from five patients with mucopolysaccharidosis (MPS). Glycosaminoglycans and lipids were isolated and chemically analyzed. Results of the present study: in the normal controls glycosaminoglycans as μg per mg protein (mean) were 2.2 in neuronal perikarya, 2.0 in astroglia, 2.1 in oligodendroglia, 3.3 in neuropile from gray matter and 3.2 in a mixed fraction from white matter. In the partially myelinated axons from gray and white matter of an 8‐month‐old infant, the concentration was 6.9 and 2.6 μg per mg protein, compared with 2.8 and 0.8 μg per mg protein, respectively, in the adult patients. It was estimated that chondroitin sulfates constituted more than one‐half of the total glycosaminoglycan. Hyaluronic acid, heparan sulfate and dermatan sulfate were also present in all cell types and fractions. Cholesterol, phospholipids, cerebrosides, sulfatide and gangliosides were present in all cell types and fractions, but differed widely in concentration. There was a four‐ to sixfold increase in the concentration of total glycosaminoglycans in the neuronal perikarya of patients with MPS IH, II and IIIA. The increased glycosaminoglycans were heparan sulfate in MPS IIIA and dermatan sulfate plus heparan sulfate in MPS IH and II. Similar changes were found in the astroglia and in the other brain fractions of those patients. The concentration of the gangliosides Gm2, Gm3, Gd3 and ceramide dihexoside was markedly increased in the neurons and other brain fractions of the same patients. The quantities of Gm3, Gm2 and Gd3 together amounted to 65% of the total gangliosides of the neurons, indicating changes of the same magnitude seen in the gangliosidoses. All these patients exhibited mental retardation. The concentration and composition of glycosaminoglycans, gangliosides and neutral hexosyl ceramides in the neuronal perikarya of the patient with MPS IS was normal. There was only a small increase of dermatan sulfate content in the neuropile, mixed fraction and myelinated axons from the white matter and some increase of ceramide dihexoside content in the myelinated axons. This patient was an adult of normal intelligence.

Mucopolysaccharidosis types I, II, IIIA and V

SummaryHistochemical and electron microscopic studies of the brains inclusive of the leptomeninges containing large blood vessels from 7 patients with mucopolysaccharidosis (MPS) I, II, IIIA and V showed marked increase in mesenchymal elements and the generalized presence of characteristic lesions around cerebral veins and arteries. The periadventitial space was greatly distended and filled with viscous fluid and numerous mononuclear cells containing large cytoplasmic vacuoles; these cells stained positively for glycosaminoglycans (GAG). In contrast, the neurons showed only a slight increase of GAG over the normal controls but contained an excessive amount of glycolipid-like material.The amount of GAG in the leptomeninges, inclusive of the large blood vessels, was 10.8, 6.5, 4.5 and 2.2 times greater in patients with MPS I, II, V and IIIA respectively, than the mean of unaffected controls. Dermatan sulfate (DS) accounted for most of the GAG increase in MPS I, II and V [mixed excretors of DS and heparan sulfate (HS)], and HS for the GAG increase in MPS IIIA (HS excretor).With the exception of the patient with MPS IIIA, whose GAG content and composition were the same in both the neural and mesenchymal elements, in all the other MPS types the mesenchymal elements contained more GAG, with a preponderance of DS.We conclude that the mesenchymal elements contribute substantially to the increased content of GAG in the brain and its coverings, mostly in the form of dermatan sulfate.

NEUROCHEMISTRY OF THE MUCOPOLYSACCHARIDOSES: BRAIN GLYCOSAMINOGLYCANS IN NORMALS AND FOUR TYPES OF MUCOPOLYSACCHARIDOSES

Glycosaminoglycan content, composition and molecular weight distribution were determined in cerebral gray and white matter, liver and spleen from normals and 7 patients with mucopolysaccharidosis; 4 were of Type I (Hurler), one Type II (Hunter), one Type IIIA (Sanfilippo A) and one Type V (Scheie).

EFFECTS OF DIFFERENT DOSAGES OF ANTICONVULSANT DRUGS ON MENTAL PERFORMANCE IN PATIENTS WITH CHRONIC EPILEPSY

Fifteen epileptic patients had their dose of anticonvulsant drugs changed twice, each time by 30‐50 per cent of the initial medication. Before the dose change, the patients were given six especially adapted mental performance tests, which were designed to measure vigilance, reaction time and certain aspects of memory. Serum drug levels were also monitored. The main results include assessment of effects of drugs on mental performance and evaluation of the psychological tests used. (1) Vigilance and reaction time test were the most useful in evaluation of effects of various doses of the medication; the memory tasks showed similar, but less definite, trends; and rote calculation and block design were of no particular value in this study. (2) On the tests for vigilance and reaction time, the greatest number of patients performed best on the lowest dose of their medication, the respective percentages being 45.8 and 56. By comparison, fewest patients performed best on their highest dose, the percentages being 16.7 for vigilance and 12.5 for reaction time; while the percentages on medium dose were 37.5 and 31.2 on the respective tests. (3) Use of well‐standardized, yet simplified, mental performance tests in combination with changes in the dosage of medication can help in reaching a compromise between acceptable seizure control and avoidance of excessive slowing of mental activity.

Mental retardation and neurologic involvement in patients with congenital retinal blindness.

Congenital retinal blindness is a recessively inherited disorder which occurs in about 10 per cent of blind children. The salient features are blindness or near‐blindness since birth or early months of life, absent or attenuated electroretinogram and generally normal appearance of the fundus initially, which changes with time to the picture of pleomorphic pigmentary degeneration of the retina. Microscopic examination reveals absence of the cones and rods and marked attenuation of the external granular layer. According to our findings, the disorder is frequently associated with mental retardation and various neurological abnormalities. Out of 13 patients studied personally, 10 were mentally retarded; 8 of these also had neurological symptoms. In 48 case reports compiled without apparent selection bias, mental retardation was present in 18 patients. The type of pathological lesions in patients with this syndrome is discussed. Electroretinogram facilitates early diagnosis which is important for appropriate long‐term management of these patients.

Acid mucopolysaccharides in the cerebrospinal fluid of patients with Hunter–Hurler's syndrome

AN IMPORTANT characteristic of the metabolic error in the patients with Hunter-Hurler’s syndrome is excessive storage of acid mucopolysaccharides (AMPS) in many organs and tissues (BRANTE, 1957; DORFMAN, 1966). In addition to hepatosplenomegaly, dwarfism and bony deformities, the affected patients generally exhibit severe neurological abnormalities which eventually culminate in a decerebrate state and death before adult years are reached. Chondroitin sulphate B (CSB) and heparitin sulphate (HS) in varying ratios accumulate in various body organs (MEYER, HOFFMAN, LINKER, GRUMBACH and SAMPSON, 1959) and are also excreted in large amounts in the urine of such patients (DEKABAN, RENNERT and HATHAWAY, 1966). Since the brain in Hunter-Hurler’s syndrome is markedly abnormal, knowledge of the content and composition of AMPS in the cerebrospinal fluid (CSF) in different variants of the diesease may prove valuable. The only pertinent report was published by FRIMAN (1967), who was unable to demonstrate the presence of AMPS in the CSF of patients with Hunter-Hurler’s syndrome. By applying a recent technique (DIFERRANTE. 1967), we have been able to demonstrate a marked increase of the A M P S in the CSF of these patients. Here, we report the values, composition, and certain chemical and physical properties of the AMPS in the CSF of patients with the clinical diagnosis of Hunter-Hurler’s syndrome.

Brain proteins: qualitative and quantitative changes, synthesis and degradation during fetal development of the rabbit.

The composition and metabolism of the proteins of the cerebral pallium of the rabbit during the final one‐third of the gestational period were measured. During this period, the brain increased in size almost 10‐fold and the migration of neuroblasts to form the cerebral cortex became complete. Concurrent with the marked structural changes, the solubility characteristics and electrophoretic distribution of various brain proteins showed little change. However, at the time of birth and in the adult, significant differences in gel electrophoresis patterns were apparent. The rate of synthesis of protein in brain slices from the fetus of 20 days gestation was 3‐fold higher per mg of tissue than in the neonate and about 30‐fold higher than in the adult. Activities of acidic and neutral proteases per unit weight were virtually the same and nearly constant throughout the late fetal period. However, during this stage, while rapid growth persists, the total protein synthetic activity of the pallium predominated over the total proteolytic activity, whereas sometime after birth the ratios of these activities reversed consequent to a shutdown of the synthetic process.

Optical rotatory dispersion of mucopolysaccharides IV. Optical rotatory dispersion and circular dichroism of glycosaminoglycans and heparan sulfate fractions from the urine of patients with mucopolysaccharidosis (Hurler Syndrome)

Abstract Genetic defects in the Hurler syndrome lead to the excessive accumulation of dermatan and heparan sulfate in many tissues and to the increase in excretion of these compounds in the urine. Patients exhibit mental detorioration, dwarfism, hepatosplenomegaly, corneal opacities and skeletal deformities. Acid mucopolysaccarides derived from the urine of heparan sulfate excretors (the Sanfilippo variant) and from mixed, dermatan sulfate and heparan sulfate excretors (the Hurler variant) were investigated. Molecular weight distributions by gel filtration and carbazole-orcinol (C/O) reactivities of the samples gave an average molecular weight of about one-third of normal for the Sanfilippo heparan sulfate which could be further separated into two fractions differing in molecular weight, sulfate content and primary structure. Optical absorption and rotary properties (from 250 to 185 mμ) of these glycosaminoglycans were studied to examine the conformational features of the accumulating substances. The results for the Sanfilippo heparan sulfate fractions indicate that two distinct heparin sulfates accumulate in this genetic defect, one with conformational structure essentially like that found in normal tissue but low in O-sulfate, and the other with heparin-like conformation and high N-sulfate content. The ultraviolet optical rotatory dispersion and circular dichroism of dermatan sulfate are greatly different from that of heparan sulfate, providing an optical method of distinguishing among Sanfilippo and other Hurler variants.