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Natural History and Identification of 3 Novel Mutations in the GNS Gene

An C. M. Jansen, MD; Henian Cao, MD; Paige Kaplan, MD; Kenneth Silver, MD, MSc, FRCPC; Gabriel Leonard, PhD; Linda De Meirleir, MD, PhD; Willy Lissens, PhD; Inge Liebaers, MD, PhD; Martin Veilleux, MD; Frederick Andermann, MD, FRCPC; Robert A. Hegele, MD, FRCPC; Eva Andermann, MD, PhD, FCCMG

Arch Neurol. 2007;64(11):1629-1634.

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.

Objectives  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.

Main Outcome Measures  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.

Author Affiliations: Neurogenetics Unit (Drs Jansen and E. Andermann) and Cognitive Neuroscience Unit (Dr Leonard), Montreal Neurological Hospital and Institute, Departments of Neurology and Neurosurgery (Drs Jansen, Leonard, Veilleux, F. Andermann, and E. Andermann), Pediatrics (Dr F. Andermann), and Human Genetics (Dr E. Andermann), McGill University, Montreal, Quebec, Canada; Departments of Pediatric Neurology (Drs Jansen and De Meirleir) and Medical Genetics (Drs Lissens and Liebaers), UZ Brussel, Brussels, Belgium; Robarts Research Institute and University of Western Ontario, London, Ontario, Canada (Drs Cao and Hegele); Department of Pediatrics, Biochemical Genetics and Metabolic Diseases Section, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (Dr Kaplan); and Department of Pediatrics, Section of Neurology, The University of Chicago Comer Children's Hospital, Chicago, Illinois (Dr Silver).