Sanfilippo syndrome type D: natural history and identification of 3 novel mutations in the GNS Gene.
BACKGROUND
Mucopolysaccharidosis type IIID (MPS-IIID), or Sanfilippo syndrome type D, is a rare autosomal recessive lysosomal storage disorder caused by mutations in the N-acetylglucosamine-6-sulfatase (GNS) gene, leading to impaired degradation of heparan sulfate.


OBJECTIVE
To report the natural history of MPS-IIID in 2 siblings described by Kaplan and Wolfe in 1987 and to study the phenotype in 2 other unrelated families with MPS-IIID. Design, Setting, and Patients Case series of 4 patients with MPS-IIID: 2 siblings followed up at the Montreal Neurological Hospital and Institute, 1 patient followed up at the UZ Brussel, and 1 patient recruited through the prenatal counseling program at the UZ Brussel.


METHODS
Clinical and molecular data collected from 3 families with enzyme-based diagnosis of MPS-IIID.


RESULTS
The course of the disease was characteristic of MPS-IIID in all patients, although survival may be longer than was previously reported. In family 1, both siblings were homozygous for a novel nonsense mutation in the GNS gene (c.1168C>T). In family 2, the proband carried a heterozygous mutation occurring in a splice recognition site in the intron 7 boundary (c.876-2A>G). The second mutation in this patient remains to be identified. In family 3, the proband was homozygous for a novel frameshift mutation in GNS due to the insertion of 5 nucleotides (c.1138_1139insGTCCT).


CONCLUSIONS
Major issues in the care of patients with MPS-IIID include behavioral problems, sleep problems, recurrent infections, dysphagia, and pain from orthopedic complications. To date, all mutations in GNS predict protein truncation, and there is no obvious genotype-phenotype correlation.
Jansen
An C M
AC
Department of Pediatric Neurology, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. anna.jansen@uzbrussel.be
Cao
Henian
H
Kaplan
Paige
P
Silver
Kenneth
K
Leonard
Gabriel
G
De Meirleir
Linda
L
Lissens
Willy
W
Liebaers
Inge
I
Veilleux
Martin
M
Andermann
Frederick
F
Hegele
Robert A
RA
Andermann
Eva
E
D000293:Adolescent; D000328:Adult; D001224:Aspartic Acid / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005192:Family Health; D005260:Female; D005973:Glutamine / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D009084:Mucopolysaccharidosis III / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D013429:Sulfatases / Q000235:genetics*
D005973:Glutamine; D001224:Aspartic Acid; D013429:Sulfatases; C018719:N-acetylglucosamine-6-sulfatase; D005998:Glycine