SANFILIPPO SYNDROME TYPE D: NATURAL HISTORY AND IDENTIFICATION OF 3 NOVEL MUTATIONS IN THE GNS GENE

Background: Mucopolysaccharidosis (MPS) IIID or Sanfilippo
syndrome type D is a rare autosomal recessive lysosomal storage
disorder caused by mutations in the GNS gene. Mutations result in
absent or decreased levels of N-acetylglucosamine 6-sulfatase,
leading to impaired degradation of heparan sulfate. We report the
natural history of MPS IIID in two siblings who were reported by
Kaplan and Wolfe in 1987. In addition, we studied the phenotype
in two other unrelated families with MPS IIID, and have identified
three novel mutations in the GNS gene.
Methods: Clinical and molecular data on three families with
enzyme based diagnosis of MPS IIID were collected.
Results: The course of the disease was characteristic for 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 (p.Gln390Ter). In Family 2,
the proband carried a heterozygous mutation occurring in a splicing
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 (p.Asp380GlyfsX9).
Conclusions: Major issues in the care of MPS IIID patients
include behavioural problems, recurrent infections, and pain from
orthopaedic complications. To date, all 7 mutations in GNS predict
premature termination of translation, and there is no obvious genotype-
phenotype correlation.