Showing papers by "Tim Wood published in 2013"

Diagnosing mucopolysaccharidosis IVA

Abstract: Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process.

Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations.

Abstract: Mucopolysaccharidosis (MPS) disorders are heterogeneous and caused by deficient lysosomal degradation of glycosaminoglycans, resulting in distinct but sometimes overlapping phenotypes. Molecular analysis was performed for a total of 355 MPS patients with MPSI (n = 15), MPSII (n = 218), MPSIIIA (n = 86), MPSIIIB (n = 20), MPSIVA (n = 6) or MPSVI (n = 10). This analysis revealed 104 previously unreported mutations: seven in IDUA (MPSI), 61 in IDS (MPSII), 19 in SGSH (MPSIIIA), 11 in NAGLU (MPSIIIB), two in GALNS (MPSIVA) and four in ARSB (MPSVI). The intergenic comparison of the mutation data for these disorders has revealed interesting differences. Whereas IDUA, IDS, NAGLU and ARSB demonstrate similar levels of mutation heterogeneity (0.6–0.675 different mutations per total alleles), SGSH and GALNS have lower levels of mutation heterogeneity (0.282 and 0.455, respectively), due to more recurrent mutations. The type of mutation also varies significantly by gene. SGSH, GALNS and ARSB mutations are usually missense (76.5 %, 81.8 % and 85 %), while IDUA has many more nonsense mutations (56 %) than the other genes (≤20%). The mutation spectrum is most diverse for IDS, including intergenic inversions and multi-exon deletions. By testing 102 mothers of MPSII patients, we determined that 22.5 % of IDS mutations are de novo. We report the allele frequency of common mutations for each gene in our patient cohort and the exonic distribution of coding sequence alterations in the IDS, SGSH and NAGLU genes, which reveals several potential “hot-spots”. This further molecular characterization of these MPS disorders is expected to assist in the diagnosis and counseling of future patients.

A Y328C missense mutation in spermine synthase causes a mild form of Snyder–Robinson syndrome

Abstract: Snyder-Robinson syndrome (SRS, OMIM: 309583) is an X-linked intellectual disability (XLID) syndrome, characterized by a collection of clinical features including facial asymmetry, marfanoid habitus, hypertonia, osteoporosis and unsteady gait. It is caused by a significant decrease or loss of spermine synthase (SMS) activity. Here, we report a new missense mutation, p.Y328C (c.1084A>G), in SMS in a family with XLID. The affected males available for evaluation had mild ID, speech and global delay, an asthenic build, short stature with long fingers and mild kyphosis. The spermine/spermidine ratio in lymphoblasts was 0.53, significantly reduced compared with normal (1.87 average). Activity analysis of SMS in the index patient failed to detect any activity above background. In silico modeling demonstrated that the Y328C mutation has a significant effect on SMS stability, resulting in decreased folding free energy and larger structural fluctuations compared with those of wild-type SMS. The loss of activity was attributed to the increase in conformational dynamics in the mutant which affects the active site geometry, rather than preventing dimer formation. Taken together, the biochemical and in silico studies confirm the p.Y328C mutation in SMS is responsible for the patients having a mild form of SRS and reveal yet another molecular mechanism resulting in a non-functional SMS causing SRS.

Snyder–Robinson syndrome: A novel nonsense mutation in spermine synthase and expansion of the phenotype

Abstract: Snyder–Robinson syndrome is a rare form of X-linked intellectual disability caused by mutations in the spermine synthase (SMS) gene, and characterized by intellectual disability, thin habitus with diminished muscle mass, osteoporosis, kyphoscoliosis, facial dysmorphism (asymmetry, full lower lip), long great toes, and nasal or dysarthric speech. Physical signs seem to evolve from childhood to adulthood. We describe the first Italian patient with Snyder–Robinson syndrome and a novel nonsense mutation in SMS (c.200G>A; p.G67X). Apart from the typical features of the syndrome, the index patient presented with an ectopic right kidney and epilepsy from the first year of age that was characterized by focal motor seizures and negative myoclonus. The clinical and molecular evaluation of this family and the review of the literature expand the phenotype of Snyder–Robinson syndrome to include myoclonic or myoclonic-like seizures (starting even in the first years of life) and renal abnormalities in affected males. © 2013 Wiley Periodicals, Inc.

Spondyloepiphyseal dysplasias and bilateral legg-calvé-perthes disease: diagnostic considerations for mucopolysaccharidoses.

Abstract: Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, MIM 253200) is an autosomal recessive lysosomal storage disease (LSD) caused by decreased activity of arylsulfatase B (N-acetylgalactosamine 4-sulfatase) enzyme resulting in dermatan sulfate accumulation; mucopolysaccharidosis type IVA (MPS IVA, Morquio syndrome A, MIM 253000) by decreased activity of N-acetylgalactosamine 6-sulfatase enzyme resulting in accumulation of keratan sulfate. Clinical symptoms include coarse facial features, joint stiffness, hepatosplenomegaly, hip osteonecrosis, and dysostosis multiplex. MPS IVA symptoms are similar but with joint hypermobility.