Abstract
BackgroundMultiple sulfatase deficiency is a rare inherited metabolic disorder caused by mutations in the SUMF1 gene. The disease remains poorly known, often leading to a late diagnosis. This study aimed to provide improved knowledge of the disease, through complete clinical, biochemical, and molecular descriptions of a cohort of unrelated patients. The main objective was to identify prognostic markers, both phenotypic and genotypic, to accelerate the diagnosis and improve patient care.MethodsThe phenotypes of ten unrelated patients were fully documented at the clinical and biochemical levels. The long-term follow-up of each patient allowed correlations of the phenotypes to the disease outcomes. Each patient’s molecular defects were also identified. Site-directed mutagenesis was used to individually express the mutants and assess their stability. Characterisation of the protein mutants was completed by in silico analyses based on sequence comparisons and structural models.ResultsThe most severe cases were characterised by the presence of non-neurological symptoms as well as the occurrence of psychomotor regression before 2 years of age. Nine novel SUMF1 mutations were identified. Clinically severe forms were often associated with SUMF1 mutations that strongly affected the protein stability and/or catalytic function as predicted from in silico and western blot analyses.ConclusionsThis detailed clinical description and follow-up of a cohort of patients, together with the molecular characterisation of their underlying defects, contribute to improved knowledge of multiple sulfatase deficiency. Predictors of a bad prognosis were the presence of several non-neurological symptoms and the onset of psychomotor regression before 2 years of age. No strict correlation existed between in vitro residual sulfatase activity and disease severity. Genotype–phenotype correlations related to previously reported mutants were strengthened. These and previous observations allow not only improved prediction of the disease outcome but also provision of appropriate care for patients, in the expectation of specific treatment development.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0244-7) contains supplementary material, which is available to authorized users.
Highlights
Multiple sulfatase deficiency is a rare inherited metabolic disorder caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene
Multiple sulfatase deficiency (MSD; MIM #272200), known as Austin disease or mucosulfatidosis, is a very rare autosomal recessive disorder. It was first described in 1964 by Austin as an atypical form of metachromatic leukodystrophy (MLD), a disease caused by deficient arylsulfatase A activity [1,2]
In addition to the neurodegenerative syndrome typically observed in MLD, the patients described by Austin presented with symptoms reminiscent of other sulfatase deficiencies, such as mucopolysaccharidoses (MPS) and X-linked ichthyosis
Summary
Multiple sulfatase deficiency is a rare inherited metabolic disorder caused by mutations in the SUMF1 gene. Multiple sulfatase deficiency (MSD; MIM #272200), known as Austin disease or mucosulfatidosis, is a very rare autosomal recessive disorder. It was first described in 1964 by Austin as an atypical form of metachromatic leukodystrophy (MLD), a disease caused by deficient arylsulfatase A activity [1,2]. Patients with MSD exhibit combined symptoms from several individual sulfatase deficiency disorders, leading to heterogeneous clinical presentations. The distinction between the severe and mild late infantile subtypes is based on the age of onset of symptoms (i.e., before or after 2 years of age), as well as the number of typical signs of individual sulfatase deficiencies. The juvenile subtype is characterised by a late onset and attenuated symptoms
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