An Italian Cohort Study Identifies Four New Pathologic Mutations in the ARSA Gene

Abstract

Metachromatic leukodystrophy is an autosomal recessive neurodegenerative disorder of the myelin metabolism due to the impaired function of the lysosomal enzyme arylsulfatase A. Three major clinical variants of metachromatic leukodystrophy (MLD) have been described: late infantile, juvenile, and late onset. The infantile form, whose clinical onset is usually before the age of 2 years, is the most frequent. The juvenile form manifests itself between 3 and 16 years and the late-onset form manifests at any time after puberty. As of today, more than 150 mutations causing MLD have been identified in the ARSA gene that encodes arylsulfatase A. In this paper, we report our experience with the diagnosis of MLD in seven Italian patients from unrelated families. We found 11 different mutations, four of which have not been previously described: c.1215_1223del9 (p.406_408del), c.601 T>C (p.Tyr201His), c.655 T>A (p.Phe219Ile), and c.87C>A (p.Asp29Glu). Our data show once more that there are still several mutations to be discovered in the ARSA gene and there are rarely repeating ones found in the population. The predictive value of the enzyme activity tests in regard to clinical manifestations is extremely limited.

Identification of a missense ARSA mutation in metachromatic leukodystrophy and its potential pathogenic mechanism

“…To further elucidate the pathogenesis of the mutations of p.E309, we built overexpression cell models of wild‐type and mutated ARSA gene. Such a cell mutation model approach has been successfully applied to several rare disease studies (Galla et al, 2013). Mock vector (Vector), wild‐type ARSA cDNA plasmid (c.925G), and missense mutated ARSA cDNA plasmid (c.925G>A, c.925G>T, c.925G>C) were transfected into HEK293 cells.…”

Mesenchymal stem cells as cellular vectors for pediatric neurological disorders

“…However, the onset of the disease may be delayed until adolescence or adulthood depending on the degree of enzyme deficiency. Recently, several new causative mutations have been identified for this disorder (Cesani et al, 2009; Galla et al, 2013; Luzi et al, 2013). …”

The natural history and burden of illness of metachromatic leukodystrophy: a systematic literature review

“…Qualitative descriptions of disease severity at baseline in untreated children were identified in 20 studies, all of which were observational studies [ 5 , 9 , 24 , 34 , 35 , 38 , 43 , 45 , 56 , 57 , 62 , 65 , 71 , 72 , 74 , 75 , 89 , 92 , 95 , 96 ]. Patients with late-infantile MLD generally presented predominantly with motor symptoms and developmental delays, whereas patients with juvenile MLD generally presented with motor, cognitive, and behavioral symptoms.…”