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Galactosialidosis: review and analysis of CTSA gene mutations.

ABSTRACT: Mutations in the CTSA gene, that encodes the protective protein/cathepsin A or PPCA, lead to the secondary deficiency of ?-galactosidase (GLB1) and neuraminidase 1 (NEU1), causing the lysosomal storage disorder galactosialidosis (GS). Few clinical cases of GS have been reported in the literature, the majority of them belonging to the juvenile/adult group of patients.The correct nomenclature of mutations for this gene is discussed through the analysis of the three PPCA/CTSA isoforms available in the GenBank database. Phenotype-genotype correlation has been assessed by computational analysis and review of previously reported single amino acid substitutions.We report the clinical and mutational analyses of four cases with the rare infantile form of GS. We identified three novel nucleotide changes, two of them resulting in the missense mutations, c.347A>G (p.His116Arg), c.775T>C (p.Cys259Arg), and the third, c.1216C>T, resulting in the p.Gln406* stop codon, a type of mutation identified for the first time in GS. An Italian founder effect of the c.114delG mutation can be suggested according to the origin of the only three patients carrying this mutation reported here and in the literature.In early reports mutations nomenclature was selected according to all CTSA isoforms (three different isoforms), thus generating a lot of confusion. In order to assist physicians in the interpretation of detected mutations, we mark the correct nomenclature for CTSA mutations. The complexity of pathology caused by the multifunctions of CTSA, and the very low numbers of mutations (only 23 overall) in relation to the length of the CTSA gene are discussed.In addition, the in silico functional predictions of all reported missense mutations allowed us to closely predict the early infantile, late infantile and juvenile phenotypes, also disclosing different degrees of severity in the juvenile phenotype.

SUBMITTER: Caciotti A

PROVIDER: S-EPMC3737020 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Galactosialidosis: review and analysis of CTSA gene mutations.

Caciotti Anna A Catarzi Serena S Tonin Rodolfo R Lugli Licia L Perez Carmen Rodriguez CR Michelakakis Helen H Mavridou Irene I Donati Maria Alice MA Guerrini Renzo R d'Azzo Alessandra A Morrone Amelia A

Orphanet journal of rare diseases 20130802

<h4>Background</h4>Mutations in the CTSA gene, that encodes the protective protein/cathepsin A or PPCA, lead to the secondary deficiency of β-galactosidase (GLB1) and neuraminidase 1 (NEU1), causing the lysosomal storage disorder galactosialidosis (GS). Few clinical cases of GS have been reported in the literature, the majority of them belonging to the juvenile/adult group of patients.<h4>Methods</h4>The correct nomenclature of mutations for this gene is discussed through the analysis of the thr ...[more]

PMID: 23915561

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Project description:BackgroundGalactosialidosis (GS) is a rare inherited lysosomal storage disorder (LSD) which is characterized by a defect in the lysosomal glycoprotein catabolism. We report, for the first time, the case of a child affected by GS presenting with recurrent episodes of extensive joint inflammation in both knee joints. The aim of this case-report is to describe the clinical presentation as well as the laboratory, radiologic and microscopic features of this unique presentation of GS. Furthermore, we explore inflammatory mechanisms potentially responsible for the origination of the arthritic joint pathology observed in our patient.Case presentationWe describe the rare case of a 12-year-old boy diagnosed with GS (late infantile form) who presented with multiple episodes of inflammatory arthritis involving both knees; no other joints were suspected for joint inflammation. Laboratory results did not indicate an autoimmune disorder. Synovial fluid tested negative for any bacterial infection and ruled out a malignancy and crystal-induced arthritis. Microscopic examination of the synovial tissue revealed numerous foamy macrophages with extensive vacuolization, consistent with the previous diagnosis of GS. Treatment consisted of aspiration of excessive joint fluid and subsequent intra-articular injection of triamcinolonhexacetonide with excellent but transient result. Given the evidence of storage products within macrophages of the inflamed synovial tissue and the absence of other etiological clues, GS itself was considered as the primary cause for the relapsing inflammatory joint pathology. According to the restricted data on articular manifestations in GS, to date, GS cannot be linked directly to joint inflammation. Nevertheless, in several other LSDs, the accumulation of storage material has been associated with numerous osteoimmunological changes that might play a role in the pathophysiology of arthritic processes.ConclusionsWe hypothesize that the articular build-up of GS storage products triggered systemic as well as local inflammatory processes, resulting in the extensive inflammatory joint pathology as observed in our patient. Future identification of other patients with GS is required to corroborate the existence of an arthritic clinical phenotype of GS and to assess the underlying pathophysiology.

Dataset Information

Galactosialidosis: review and analysis of CTSA gene mutations.

Publications

Galactosialidosis: review and analysis of CTSA gene mutations.

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