title: Infantile Sialic Acid Storage Disease: Two Unrelated Inuit Cases Homozygous for a Common Novel SLC17A5 Mutation.
abstract: Infantile sialic acid storage disease (ISSD) is a lysosomal storage disease characterized by accumulation of covalently unlinked (free) sialic acid in multiple tissues. ISSD and Salla disease (a predominantly neurological disorder) are allelic disorders caused by recessive mutations of a lysosomal anionic monosaccharide transporter, SLC17A5. While Salla disease is common in Finland due to a founder-effect mutation (p.Arg39Cys), ISSD is comparatively rare in all populations studied.Here, we describe the clinical and molecular features of two unrelated Canadian Inuit neonates with a virtually identical presentation of ISSD. Both individuals presented antenatally with fetal hydrops, dying shortly following delivery. Urinary free sialic acid excretion was markedly increased in the one case in which urine could be obtained for testing; postmortem examination showed a picture of widespread lysosomal storage in both. Both children were homozygous for a novel splice site mutation (NM_012434:c.526-2A>G) resulting in skipping of exon 4 and an ensuing frameshift. Analysis of a further 129 pan-Arctic Inuit controls demonstrated a heterozygous carrier rate of 1/129 (~0.4 %) in our sample. Interestingly, lysosomal enzyme studies showed an unexplained ninefold increase in neuraminidase activity, with lesser elevations in the activities of several other lysosomal enzymes. Our results raise the possibility of a common founder mutation presenting as hydrops in this population. Furthermore, if confirmed in subsequent cases, the marked induction of neuraminidase activity seen here may prove useful in the clinical diagnosis of ISSD.
authors.affiliation: Division of Metabolics and Newborn Screening, University of Ottawa, Children's Hospital of Eastern Ontario, 401 Smyth Road, K1H 8L1, Ottawa, ON, Canada.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Lines
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Rupar
authors.forename: Jack W
authors.initials: JW
authors.lastname: Rip
authors.forename: Berivan
authors.initials: B
authors.lastname: Baskin
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ray
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: David
authors.initials: D
authors.lastname: Grynspan
authors.forename: Jean
authors.initials: J
authors.lastname: Michaud
authors.forename: Michael T
authors.initials: MT
authors.lastname: Geraghty
references.citation: Neurology. 2010 Jan 26;74(4):302-5
references.pmid: 20101035
references.citation: Brain Dev. 1996 Mar-Apr;18(2):153-6
references.pmid: 8733911
references.citation: Mol Genet Metab. 2007 Dec;92(4):371-4
references.pmid: 17933575
references.citation: J Med Genet. 2005 Nov;42(11):829-36
references.pmid: 15805149
references.citation: FEBS J. 2005 May;272(10):2545-56
references.pmid: 15885103
references.citation: Acta Paediatr. 2002;91(12):1324-7
references.pmid: 12578289
references.citation: Pediatr Neurol. 1988 Jul-Aug;4(4):207-12
references.pmid: 3072006
references.citation: Acta Paediatr. 2003 Nov;92(11):1357-8
references.pmid: 14696864
references.citation: Mol Genet Metab. 2004 Jun;82(2):167-72
references.pmid: 15172005
references.citation: Ann Neurol. 2009 Jun;65(6):753-7
references.pmid: 19557856
references.citation: Am J Hum Genet. 2000 Oct;67(4):832-40
references.pmid: 10947946
references.citation: Turk J Pediatr. 2009 Nov-Dec;51(6):605-9
references.pmid: 20196397
references.citation: Neurogenetics. 2005 Dec;6(4):195-9
references.pmid: 16170568
references.citation: Hum Genet. 1985;71(2):155-9
references.pmid: 4043964
references.citation: Eur J Pediatr. 1987 Mar;146(2):195-8
references.pmid: 3569361
references.citation: Clin Genet. 2002 Jun;61(6):443-7
references.pmid: 12121352
references.citation: J Biol Chem. 2005 Jan 14;280(2):1408-16
references.pmid: 15516337
references.citation: Am J Med Genet. 1999 Feb 19;82(5):385-91
references.pmid: 10069709
references.citation: Nat Genet. 1999 Dec;23(4):462-5
references.pmid: 10581036
references.citation: Pediatr Int. 2003 Apr;45(2):199-200
references.pmid: 12709150
references.citation: EMBO J. 2004 Nov 24;23(23):4560-70
references.pmid: 15510212
references.citation: Neuropediatrics. 1986 Feb;17(1):44-7
references.pmid: 3960283
references.citation: Clin Genet. 1986 May;29(5):417-24
references.pmid: 3742847
references.citation: Neurobiol Dis. 2005 Aug;19(3):351-65
references.pmid: 16023578
references.citation: Biochem J. 2004 Jun 1;380(Pt 2):425-33
references.pmid: 14992689
references.citation: Biol Cell. 2008 Sep;100(9):551-9
references.pmid: 18399798
references.citation: J Pediatr. 2011 Jan;158(1):165, 165.e1
references.pmid: 20728092