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Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations.

ABSTRACT: Morquio A (Mucopolysaccharidosis IVA; MPS IVA) is an autosomal recessive lysosomal storage disorder caused by partial or total deficiency of the enzyme galactosamine-6-sulfate sulfatase (GALNS; also known as N-acetylgalactosamine-6-sulfate sulfatase) encoded by the GALNS gene. Patients who inherit two mutated GALNS gene alleles have a decreased ability to degrade the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate, thereby causing GAG accumulation within lysosomes and consequently pleiotropic disease. GALNS mutations occur throughout the gene and many mutations are identified only in single patients or families, causing difficulties both in mutation detection and interpretation. In this study, molecular analysis of 163 patients with Morquio A identified 99 unique mutations in the GALNS gene believed to negatively impact GALNS protein function, of which 39 are previously unpublished, together with 26 single-nucleotide polymorphisms. Recommendations for the molecular testing of patients, clear reporting of sequence findings, and interpretation of sequencing data are provided.

SUBMITTER: Morrone A

PROVIDER: S-EPMC4203673 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations.

Morrone A A Tylee K L KL Al-Sayed M M Brusius-Facchin A C AC Caciotti A A Church H J HJ Coll M J MJ Davidson K K Fietz M J MJ Gort L L Hegde M M Kubaski F F Lacerda L L Laranjeira F F Leistner-Segal S S Mooney S S Pajares S S Pollard L L Ribeiro I I Wang R Y RY Miller N N

Molecular genetics and metabolism 20140320 2

Morquio A (Mucopolysaccharidosis IVA; MPS IVA) is an autosomal recessive lysosomal storage disorder caused by partial or total deficiency of the enzyme galactosamine-6-sulfate sulfatase (GALNS; also known as N-acetylgalactosamine-6-sulfate sulfatase) encoded by the GALNS gene. Patients who inherit two mutated GALNS gene alleles have a decreased ability to degrade the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate, thereby causing GAG accumulation within lysosomes and consequ ...[more]

PMID: 24726177

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Project description:Mucopolysaccharidosis (MPS) IVA is a rare lysosomal storage disorder with multiple skeletal and non-skeletal abnormalities requiring multiple surgical interventions. It is well known that patients with MPS IVA suffer from tachycardia, but cardiac and hemodynamic alterations have not been reported to date. We investigated the cardiovascular and hemodynamic alterations in patients with MPS IVA and developed a possible patho-mechanism for cardiovascular deterioration during anesthesia.In this observational study, serial cardiac examinations were performed in 54 patients with MPS IVA who were followed at the Children's Hospital of the Mainz Medical University (Mainz, Germany) between 1991 and 2014 (follow-up 1-24 years; median 5.8 years). Results were compared with data from a large central European cohort of more than 2000 healthy infants and children.None of the patients had arterial hypertension, but 4% had evidence of increased pulmonary artery pressure. Patients developed aortic root extension up to 6.9 standard deviations above normal. Left-sided valve leaflet thickening occurred in 26 patients (five with valve disease). Patients had lower left ventricular dimensions (z: -1.02±0.1), lower stroke volumes (z: -2.3±0.17), lower left ventricular mass (z: -1.5±0.21), but higher wall thickness (z: +0.8±0.16), and higher work index (z: +2.5±0.2) compared to healthy control subjects. Cardiac output was preserved by an increase in heart rate of 21%. Sixty % of patients showed impaired diastolic filling; heart rate (99.0±1.8 vs. 92.0±2.1 bpm), age (18.0±1.8 vs. 14.2±1 years), and cardiothoracic ratio (61.6±3.6% vs. 55±4.2%) of these patients were higher compared to those with normal filling.The results of this study suggest an age-progressive disproportion of the intra-thoracic organs of patients with MPS IVA, which is accompanied by aortic root extension and thickened left ventricles, with reduced stroke volumes, impaired diastolic filling patterns, and increased heart rates.

Dataset Information

Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations.

Publications

Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations.

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