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Neuropediatrics 2005; 36(3): 171-180
DOI: 10.1055/s-2005-865608
Original Article

Georg Thieme Verlag KG Stuttgart · New York

Prosaposin Deficiency - a Rarely Diagnosed, Rapidly Progressing, Neonatal Neurovisceral Lipid Storage Disease. Report of a Further Patient

M. Elleder1 , M. Jeřábková1 , A. Befekadu1 , M. Hřebíček1 , L. Berná1 , J. Ledvinová1 , H. Hůlková1 , H. Rosewich2 , N. Schymik3 , B. C. Paton4 , 5 , K. Harzer6
  • 1Institute of Inherited Metabolic Disorders, Charles University, First Faculty of Medicine, Prague, Czech Republic
  • 2Department of Pediatrics and Pediatric Neurology, Georg August University, Göttingen, Germany
  • 3Department of Pathology and Neuropathology, Klinikum Lippe-Detmold, Detmold, Germany
  • 4Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia
  • 5Department of Paediatrics, University of Adelaide, Adelaide, South Australia
  • 6Department of Neuropediatrics and Child Development, Universitäts-Kinderklinik, Tübingen, Germany
Further Information

Publication History

Received: January 26, 2005

Accepted after Revision: March 23, 2005

Publication Date:
09 June 2005 (online)

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Abstract

An infant presented with multifocal myoclonus and cyanotic hypoxemia immediately after birth, and severe feeding problems, a protein-losing enteropathy, massive ascites and grand-mal epilepsy marked his rapid downhill course, with death at 17 weeks. At 2 weeks, brain MRI revealed grey matter heterotopias in the parieto-occipital regions suggestive of a cortical morphogenetic disorder. In cultured skin fibroblasts, lipid storage and reduced activities of ceramidase, galactosylceramide β-galactosidase and glucosylceramide β-glucosidase were evident. Autopsy disclosed generalised lysosomal lipid storage with macrophages and adrenal cortex prominently affected. The pattern of stored lipids in cultured fibroblasts and in dewaxed spleen tissue blocks was compatible with a diagnosis of prosaposin (pSap) deficiency (pSap-d). Neuropathologically, there was a pronounced generalised neurolysosomal storage combined with a severe depletion of cortical neurons and extreme paucity of myelin and oligodendroglia. This pathology, in particular the massive neuronal loss, differed from that in other neurolipidoses and could be explained by the reduced hydrolysis of multiple sphingolipids and the loss of pSap's neurotrophic function. The absence of immunostainable saposins on tissue sections and the presence of a homozygous c.1 A > T mutation in the prosaposin gene confirmed the diagnosis. PSap-d may be an underdiagnosed condition in infants with severe neurological and dystrophic signs starting immediately after birth.

Key words

Prosaposin - saposin - sphingolipid storage - mutation - sphingolipid loading tests

References

  • 1 Asfaw B, Schindler D, Ledvinová J, Černý B, Šmíd F, Conzelmann E. Degradation of blood group A glycolipid A-6 - 2 by normal and mutant human skin fibroblasts.  J Lip Res. 1998;  39 1768-1780
    PubMedGoogle Scholar
  • 2 Bradová V, Šmíd F, Ulrich-Bott B, Roggendorf W, Paton B C, Harzer K. Prosaposin deficiency: further characterization of the sphingolipid activator protein-deficient sibs.  Hum Genet. 1993;  92 143-152
    PubMedGoogle Scholar
  • 3 Campana W M, Hiraiwa M, O'Brien J S. Prosaptide activates the MAPK pathway by a G-protein-dependent mechanism essential for enhanced sulfatide synthesis by Schwann cells.  FASEB J. 1998;  12 307-314
    PubMedGoogle Scholar
  • 4 Chatelut M, Harzer K, Christomanou H, Feunteun J, Pieraggi M T, Paton B C, Kishimoto Y, O'Brien J S, Basile J-P, Thiers J-C, Salvayre R, Levade T. Model SV40-transformed fibroblast lines for metabolic studies of human prosaposin and acid ceramidase deficiencies.  Clin Chim Acta. 1997;  262 61-76
    CrossrefPubMedGoogle Scholar
  • 5 Chomzynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.  Anal Biochem. 1987;  162 156-159
    PubMedGoogle Scholar
  • 6 Ciaffoni F, Tatti M, Salvioli R, Vaccaro A M. Interaction of saposin D with membranes: effect of anionic phospholipids and sphingolipids.  Biochem J. 2003;  373 785-792
    CrossrefPubMedGoogle Scholar
  • 7 Cormand B, Montfort M, Chabas A, Vilageliu L, Grinberg D. Genetic fine localization of the beta-glucocerebrosidase (GBA) and prosaposin (PSAP) genes: implications for Gaucher disease.  Hum Genet. 1997;  100 75-79
    PubMedGoogle Scholar
  • 8 Elleder M, Lojda Z. Studies in lipid histochemistry. X. Lipids in paraffin section.  Histochemie. 1973;  34 143-156
    CrossrefPubMedGoogle Scholar
  • 9 Elleder M, Šmíd F. Adrenal changes in Niemann-Pick disease: differences between sphingomyelinase deficiency and type C.  Acta Histochem. 1985;  76 163-176
    PubMedGoogle Scholar
  • 10 Fujita N, Suzuki K, Vanier M T, Popko B, Maeda N, Klein A, Henseler M, Sandhoff K, Nakayasu H, Suzuki K. Targeted disruption of the mouse sphingolipid activator protein gene: a complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids.  Hum Mol Genet. 1996;  5 711-725
    CrossrefPubMedGoogle Scholar
  • 11 Haltia M, Rapola J, Santavuori P. Infantile type of so-called neuronal ceroid-lipofuscinosis. Histological and electron microscopic studies.  Acta Neuropathol. 1973;  26 157-170
    CrossrefPubMedGoogle Scholar
  • 12 Harzer K. Enzymic diagnosis in 27 cases with Gaucher's disease.  Clin Chim Acta. 1980;  106 9-15
    CrossrefPubMedGoogle Scholar
  • 13 Harzer K. Prenatal enzymic diagnosis in 24 pregnancies with risk of Krabbe disease.  Clin Chim Acta. 1982;  122 21-28
    CrossrefPubMedGoogle Scholar
  • 14 Harzer K, Benz H U. A simple sphingomyelinase determination for Niemann-Pick disease: differential diagnosis of types A, B and C.  J Neurochem. 1973;  21 999-1001
    PubMedGoogle Scholar
  • 15 Harzer K, Hiraiwa M, Paton B C. Saposins (sap) A and C activate the degradation of galactosylsphingosine.  FEBS Lett. 2001;  508 107-110
    CrossrefPubMedGoogle Scholar
  • 16 Harzer K, Paton B C, Christomanou H, Chatelut M, Levade T, Hiraiwa M, O'Brien J S. Saposins (sap) A and C activate the degradation of galactosylceramide in living cells.  FEBS Lett. 1997;  417 270-274
    CrossrefPubMedGoogle Scholar
  • 17 Harzer K, Paton B C, Poulos A, Kustermann-Kuhn B, Roggendorf W, Grisar T, Popp M. Sphingolipid activator protein deficiency in a 16-week-old atypical Gaucher disease patient and his fetal sibling: biochemical signs of combined sphingolipidoses.  Eur J Pediatr. 1989;  149 31-39
    PubMedGoogle Scholar
  • 18 Hazkani-Covo E, Altman N, Horowitz M, Graur D. The evolutionary history of prosaposin: two successive tandem-duplication events gave rise to the four saposin domains in vertebrates.  J Mol Evol. 2002;  54 30-34
    PubMedGoogle Scholar
  • 19 Hiraiwa M, Campana W M, Mizisin A P, Mohiuddin L, O'Brien J S. Prosaposin: a myelinotrophic protein that promotes expression of myelin constituents and is secreted after nerve injury.  Glia. 1999;  26 353-360
    CrossrefPubMedGoogle Scholar
  • 20 Hůlková H, Červenková M, Ledvinová J, Tocháčková M, Hřebíček M, Poupětová H, Befekadu A, Berná L, Paton B C, Harzer K, Böör A, Šmíd F, Elleder M. A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation.  Hum Mol Genet. 2001;  10 927-940
    CrossrefPubMedGoogle Scholar
  • 21 Kattner E, Schäfer A, Harzer K. Hydrops fetalis: manifestation in lysosomal storage diseases including Farber disease.  Eur J Pediatr. 1997;  156 292-295
    CrossrefPubMedGoogle Scholar
  • 22 Laurent-Matha V, Lucas A, Huttler S, Sandhoff K, Garcia M, Rochefort H. Procathepsin D interacts with prosaposin in cancer cells but its internalization is not mediated by LDL receptor-related protein.  Exp Cell Res. 2002;  277 210-219
    CrossrefPubMedGoogle Scholar
  • 23 Lefrancois S, May T, Knight C, Bourbeau D, Morales C R. The lysosomal transport of prosaposin requires the conditional interaction of its highly conserved D domain with sphingomyelin.  J Biol Chem. 2002;  277 17188-17199
    CrossrefPubMedGoogle Scholar
  • 24 Lefrancois S, Zeng J, Hassan A J, Canuel M, Morales C R. The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin.  EMBO J. 2003;  22 6430-6437
    CrossrefPubMedGoogle Scholar
  • 25 Matsuda J, Vanier M T, Saito Y, Tohyama J, Suzuki K, Suzuki K. A mutation in the saposin A domain of the sphingolipid activator protein (prosaposin) gene results in a late-onset, chronic form of globoid cell leukodystrophy in the mouse.  Hum Mol Genet. 2001;  10 1191-1199
    CrossrefPubMedGoogle Scholar
  • 26 Matsuda J, Kido M, Tadano-Aritomi K, Ishizuka I, Tominaga K, Toida K, Takeda E, Suzuki K, Kuroda Y. Mutation in saposin D domain of sphingolipid activator protein gene causes urinary system defects and cerebellar Purkinje cell degeneration with accumulation of hydroxy fatty acid-containing ceramide in the mouse.  Hum Mol Genet. 2004;  13 2709-2723
    CrossrefPubMedGoogle Scholar
  • 27 Millat G, Verot L, Rodriguez-Lafrasse C, DiMarco J N, Rimet Y, Poujol A, Girard N, Monges G, Livet M O, Vanier M T. Fourth reported family with prosaposin deficiency. Elleder M, Ledvinová J, Hřebíček M, Poupětová H, Kožich V Book of Abstracts 14th ESGLD Workshop (September 18th-21st, 2003). Poděbrady/Prague; Guarant Ltd 2003: 81
    Google Scholar
  • 28 Morales C R, Zhao Q, El-Alfy M, Suzuki K. Targeted disruption of the mouse prosaposin gene affects the development of the prostate gland and other male reproductive organs.  J Androl. 2000;  21 765-775
    PubMedGoogle Scholar
  • 29 O'Brien J S, Kretz K A, Dewji N, Wenger D A, Esch F, Fluharty A L. Coding of two sphingolipid activator proteins (SAP1 and SAP-2) by same genetic locus.  Science. 1988;  241 1098-1101
    PubMedGoogle Scholar
  • 30 Paton B C, Hughes J L, Harzer K, Poulos A. Immunocytochemical localization of sphingolipid activator protein 2 (SAP-2) in normal and SAP-deficient fibroblasts.  Eur J Cell Biol. 1990;  51 157-164
    PubMedGoogle Scholar
  • 31 Paton B C, Schmid B, Kustermann-Kuhn B, Poulos A, Harzer K. Additional biochemical findings in a patient and fetal sibling with a genetic defect in the sphingolipid activator protein (SAP) precursor, prosaposin. Evidence for a deficiency in SAP-1 and for a normal lysosomal neuraminidase.  Biochem J. 1992;  285 481-488
    PubMedGoogle Scholar
  • 32 Paton B C, Schneider-Jakob H R, Kopitz J, Harzer K, Poulos Cantz A M. Further evidence that human lysosomal sialidase is not derived from prosaposin. Prosaposin biosynthesis and ganglioside sialidase studies in prosaposin- and sialidase-deficient fibroblast lines.  Biol Chem Hoppe-Seyler. 1994;  375 25-29
    PubMedGoogle Scholar
  • 33 Qi X, Grabowski G A. Differential membrane interactions of saposins A and C: implications for the functional specificity.  J Biol Chem. 2001;  276 27010-27017
    CrossrefPubMedGoogle Scholar
  • 34 Qi X, Qin W, Sun Y, Kondoh K, Grabowski G A. Functional organization of saposin C. definition of neurotrophic and acid beta-glucosidase activation regions.  J Biol Chem. 1996;  271 6874-6880
    CrossrefPubMedGoogle Scholar
  • 35 Rende M, Brizi E, Donato R, Provenzano C, Bruno R, Mizisin A P, Garrett R S, Calcutt N A, Campana W M, O'Brien J S. Prosaposin is immunolocalized to muscle and prosaptides promote myoblast fusion and attenuate loss of muscle mass after nerve injury.  Muscle Nerve. 2001;  24 799-808
    PubMedGoogle Scholar
  • 36 Sadeghlar F, Remmel N, Breiden B, Klingenstein R, Schwarzmann G, Sandhoff K. Physiological relevance of sphingolipid activator proteins in cultured human fibroblasts.  Biochimie. 2003;  85 439-448
    CrossrefPubMedGoogle Scholar
  • 37 Sandhoff K, Kolter T, Harzer K. Sphingolipid activator proteins. Scriver CR, Beaudet AL, Sly WS, Valle D The Metabolic and Molecular Bases of Inherited Disease. New York; McGraw-Hill 2001: 3371-3388
    Google Scholar
  • 38 Schmid B, Paton B C, Sandhoff K, Harzer K. Metabolism of GM1 ganglioside in cultured skin fibroblasts: anomalies in gangliosidoses, sialidoses, and sphingolipid activator protein (SAP, saposin) 1 and prosaposin deficient disorders.  Hum Genet. 1992;  89 513-518
    PubMedGoogle Scholar
  • 39 Schnabel D, Schröder M, Fürst W, Klein A, Hurwitz R, Zenk T, Weber J, Harzer K, Paton B C, Poulos A, Suzuki K, Sandhoff K. Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is caused by a mutation in the initiation codon of their common gene.  J Biol Chem. 1992;  267 3312-3315
    PubMedGoogle Scholar
  • 40 Soeda S, Hiraiwa M, O'Brien J S, Kishimoto Y. Binding of cerebrosides and sulfatides to saposins A-D.  J Biol Chem. 1993;  268 18519-18523
    PubMedGoogle Scholar
  • 41 Sun Y, Qi X, Grabowski G A. Saposin C is required for normal resistance of acid beta-glucosidase to proteolytic degradation.  J Biol Chem. 2003;  278 31918-31923
    CrossrefPubMedGoogle Scholar
  • 42 Sun Y, Qi X, Witte D P, Ponce E, Kondoh K, Quinn B, Grabowski G A. Prosaposin: threshold rescue and analysis of the “neuritogenic” region in transgenic mice.  Mol Genet Metab. 2002;  76 271-286
    CrossrefPubMedGoogle Scholar
  • 43 Suopanki J, Tyynela J, Baumann M, Haltia M. The expression of palmitoyl-protein thioesterase is developmentally regulated in neural tissues but not in nonneural tissues.  Mol Genet Metab. 1999;  66 290-293
    CrossrefPubMedGoogle Scholar
  • 44 Svennerholm L. The quantitative estimation of cerebrosides in nervous tissue.  J Neurochem. 1956;  1 42-53
    PubMedGoogle Scholar
  • 45 Vaccaro A M, Salvioli R, Tatti M, Ciaffoni F. Saposins and their interaction with lipids.  Neurochem Res. 1999;  24 307-314
    PubMedGoogle Scholar

Prof. Dr. K. Harzer

Universitäts-Kinderklinik
Neurometabolisches Labor

Hoppe-Seyler-Straße 1

72076 Tübingen

Germany

Email: Harzer-Rottenburg@t-online.de

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