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1/145. fucosidosis: a neuropathological study.

    The involvement of the central nervous system in fucosidosis is related to severe lesions of both nerve and glial cells. The morphology of cells degeneration is characterized by both vacuoli containing water-soluble fuco-derivatives (fuco-oligosaccharides) and/or granular substances probably constituted by fuco-sphingolipds. The cerebral cortex is the most severely affected. The involvement of the white matter is related to the glial cells degeneration. The relationship between the morphology of nerve and glial cells lesions, and the accumulation of oligosaccharides and sphingolipids following the absence of alpha-l-fucosidase, is briefly discussed. ( info)

2/145. Leukocyte adhesion deficiency II syndrome, a generalized defect in fucose metabolism.

    Leukocyte adhesion deficiency II has been described in only 2 patients; herein we report extensive investigation of another patient. The physical stigmata were detected during prenatal ultrasonographic investigation. Sialyl-Lewis X (sLex) was absent from the surface of polymorphonuclear neutrophils, and cell binding to E- and p-selectin was severely impaired, causing an immunodeficiency. The elevation of peripheral neutrophil counts occurred within several days after birth. A severe hypofucosylation of glycoconjugates bearing fucose in different glycosidic links was present in all cell types investigated, demonstrating that leukocyte adhesion deficiency II is not only a disorder of leukocytes but a generalized inherited metabolic disease affecting the metabolism of fucose. ( info)

3/145. Pontocerebellar hypoplasia associated with respiratory-chain defects.

    Pontocerebellar hypoplasias are congenital disorders of brain morphogenesis which include such diverse etiologies as carbohydrate-deficient glycoprotein syndrome type 1, cerebromuscular dystrophies (walker-warburg syndrome, Fukuyama syndrome, muscle-eye-brain disease) and at least two types of autosomal recessive neurodegenerations known as pontocerebellar hypoplasia type I and II. Pontocerebellar hypoplasia type 1 is a lethal phenotype and clinical features include congenital contractures, respiratory insufficiency, central and peripheral motor dysfunction and spinal anterior horn degeneration. Type 2 is characterized by progressive microcephaly, extrapyramidal dyskinesia and normal spinal cord findings. In this paper, we describe a girl, born at 33 weeks of gestation, presenting with respiratory insufficiency and multiple contractures. MRI scan of the brain demonstrated pontocerebellar hypoplasia and cortical and diffuse periventricular white matter abnormalities. Postmortem examination showed pontocerebellar hypoplasia with extensive gliosis of the periventricular white matter and of the basal ganglia with normal spinal cord findings. histology of skeletal muscle was normal. Biochemical analysis demonstrated multiple deficiencies of respiratory chain enzymes in skin fibroblasts. This case demonstrates a lethal phenotype of pontocerebellar hypoplasia without spinal cord abnormalities associated with a respiratory-chain disorder. The diagnostic workup in a patient whose brain image shows pontocerebellar hypoplasia should include a search for respiratory-chain impairment. ( info)

4/145. Onset of sucrase-isomaltase deficiency in late adulthood.

    sucrase-isomaltase deficiency is a rare disorder usually manifested as diarrhea in infancy. The presentation of such a deficiency in adulthood is even more rare, particularly when the individual has no history of childhood diarrhea. After a literature search, the 59-yr-old patient we report is the oldest to have been identified with this condition. The difficulties encountered in diagnosis when such a case occurs at this age that have not previously been reported are highlighted. ( info)

5/145. Leukoencephalopathy associated with a disturbance in the metabolism of polyols.

    In vivo proton magnetic resonance spectroscopy of the brain demonstrated highly elevated levels of arabitol and ribitol in a 14-year-old boy with a white matter disorder and neuropathy of unknown origin. These polyols also were shown to be elevated in body fluids, suggesting an inborn error in polyol metabolism. The strong plasma/ cerebrospinal fluid/brain gradient, with concentrations increasing in that order, suggests a primary neurometabolic disorder. Thus far, a basic enzyme defect has not been identified. ( info)

6/145. A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.

    Glucosidase I is an important enzyme in N-linked glycoprotein processing, removing specifically distal alpha-1,2-linked glucose from the Glc3Man9GlcNAc2 precursor after its en bloc transfer from dolichyl diphosphate to a nascent polypeptide chain in the endoplasmic reticulum. We have identified a glucosidase I defect in a neonate with severe generalized hypotonia and dysmorphic features. The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d. The accumulation of the tetrasaccharide Glc(alpha1-2)Glc(alpha1-3)Glc(alpha1-3)Man in the patient's urine indicated a glycosylation disorder. Enzymological studies on liver tissue and cultured skin fibroblasts revealed a severe glucosidase I deficiency. The residual activity was <3% of that of controls. Glucosidase I activities in cultured skin fibroblasts from both parents were found to be 50% of those of controls. tissues from the patient subjected to SDS-PAGE followed by immunoblotting revealed strongly decreased amounts of glucosidase I protein in the homogenate of the liver, and a less-severe decrease in cultured skin fibroblasts. Molecular studies showed that the patient was a compound heterozygote for two missense mutations in the glucosidase I gene: (1) one allele harbored a G-->C transition at nucleotide (nt) 1587, resulting in the substitution of Arg at position 486 by Thr (R486T), and (2) on the other allele a T-->C transition at nt 2085 resulted in the substitution of Phe at position 652 by Leu (F652L). The mother was heterozygous for the G-->C transition, whereas the father was heterozygous for the T-->C transition. These base changes were not seen in 100 control dna samples. A causal relationship between the alpha-glucosidase I deficiency and the disease is postulated. ( info)

7/145. The ultrastructure of hepatocytes in alpha-1-antitrypsin deficiency with the genotype Pi--.

    The ultrastructural appearance of the endoplasmic reticulum of the hepatocytes was found to be normal in a 5-year-old girl with alpha-1-antitrypsin deficiency with the genotype Pi--. The liver ultrastructure of this variant is therefore different from that of alpha-1-antitrypsin deficiency with the genotype PiZZ in which aggregates of an abnormal, unsecreted alpha-1-antitrypsin accumulate in the endoplasmic reticulum of the hepatocytes. The normal appearance of the endoplasmic reticulum in alpha-1-antitrypsin deficiency with the genotype Pi-- is compatible with the hypothesis, in this variant, synthesis of alpha-1-antitrypsin is completely, or nearly completely, absent; an alternative hypothesis would be that an abnormal alpha-1-antitrypsin is produced by the liver and secreted into the plasma, but disappears rapidly from the plasma. ( info)

8/145. Congenital sucrase-isomaltase deficiency arising from cleavage and secretion of a mutant form of the enzyme.

    Congenital sucrase-isomaltase deficiency (CSID) is an autosomal recessive human intestinal disorder that is clinically characterized by fermentative diarrhea, abdominal pain, and cramps upon ingestion of sugar. The symptoms are the consequence of absent or drastically reduced enzymatic activities of sucrase and isomaltase, the components of the intestinal integral membrane glycoprotein sucrase-isomaltase (SI). Several known phenotypes of CSID result from an altered posttranslational processing of SI. We describe here a novel CSID phenotype, in which pro-SI undergoes an unusual intracellular cleavage that eliminates its transmembrane domain. Biosynthesis of pro-SI in intestinal explants and in cells transfected with the SI cDNA of this phenotype demonstrated a cleavage occurring within the endoplasmic reticulum due to a point mutation that converts a leucine to proline at residue 340 of isomaltase. Cleaved pro-SI is transported to and processed in the golgi apparatus and is ultimately secreted into the exterior milieu as an active enzyme. To our knowledge this is the first report of a disorder whose pathogenesis results not from protein malfolding or mistargeting, but from the conversion of an integral membrane glycoprotein into a secreted species that is lost from the cell surface. ( info)

9/145. Response to LH-RH and clomiphene citrate in two women with the Prader-Labhart-Willi syndrome.

    Two women with the Prader-Labhart-Willi syndrome are presented. The gonadotropin response to LH-RH administration was studied prior to, immediately following, and 6 months after a 6-week trial of clomiphene citrate, 200 mg per day for 21 days in divided doses, followed by 100 mg for 21 days in divided doses, followed by 100 mg per day for 14 days in divided doses, and followed by 50 mg per day in a single dose for an additional 14 days. During therapy, the basal gonadotropin and estradiol concentrations rose from prepubertal levels to those of mature women in midmenstrual cycle. However, 6 months after cessation of treatment, the basal gondadotropin and estradiol levels had returned to the prepubertal range. The initial response to LH-RH in the 2 patients differed in that one was clearly prepubertal and the other indistinguishable from the broad range of the adult normal response. The LY and FSH responses to LH-RH administration was greater after 6 weeks of clomiphene citrate therapy than they were either before (both patients) or 6 months after treatment (1 patient). We conclude that there is heterogeneity in the response to LH-RH administration in the Prader-Labhart-Willi Syndrome, just as there is in other syndromes of hypogonadotropic hypogonadism. A normal adult response of gonadotropins to the administration of LH-RH was acheived during clomiphene citrate therapy. ( info)

10/145. Lectin analyses of glycoprotein hormones in patients with congenital disorders of glycosylation.

    OBJECTIVE: The congenital disorders of glycosylation (CDGs) are progressive multisystemic disorders characterized by a heterogeneous deficiency of the carbohydrate moieties in various structural and circulating glycoproteins, representing a natural model for glycoprotein hormone studies. Here, we studied the carbohydrate moiety of circulating glycoprotein hormones in four patients with a clinical suspicion of CDGs. methods: The diagnosis of CDG-I was confirmed in two out of the four cases by transferrin isoelectrofocusing (IEF) and/or carbohydrate-deficient transferrin (CDT) test. The carbohydrate moiety of serum endocrine-related glycoproteins was investigated by means of ricin (immunopurified thyrotropin (TSH)) and concanavalin a (Con-A) (TSH, follicle-stimulating hormone, alpha-subunit and thyroglobulin) lectin affinity chromatography measurement. RESULTS: CDT concentrations were very high in the two patients with CDG-I and moderately enhanced in the remaining two. In the two CDG-I patients, ricin analysis of immunopurified TSH showed a severe impairment of lectin binding, both before and after neuroaminidase treatment, indicating a nearly complete lack of terminal sialic acid and galactose residues. In these two cases, Con-A analysis showed a significant prevalence of firmly bound isoforms with poorly processed carbohydrate chains. In the remaining two cases with unknown CDG classification, TSH binding pattern to ricin was modestly affected and Con-A analysis showed the prevalence of weakly bound glycoprotein isoforms. CONCLUSIONS: The results of ricin analyses in all four patients were consistent with the CDT test and/or serum transferrin IEF. The severe alteration of TSH binding pattern to ricin seems to be characteristic of CDG-I. Nevertheless, TSH biological properties are not severely altered, as normal thyroid function was found in both cases. ( info)
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