Comprehensive clinical, biochemical, radiological and genetic analysis of 28 Turkish cases with suspected metachromatic leukodystrophy and their relatives

Faruk Pekgül; Nesibe Gevher Eroğlu-Ertuğrul; Can Ebru Bekircan-Kurt; Sevim Erdem-Ozdamar; Arda Çetinkaya; Ersin Tan; Bahadır Konuşkan; Ergun Karaağaoğlu; Meral Topçu; Nurten Ayşe Akarsu; Kader K Oguz; Banu Anlar; Hatice Asuman Özkara

doi:10.1016/j.ymgmr.2020.100688

Comprehensive clinical, biochemical, radiological and genetic analysis of 28 Turkish cases with suspected metachromatic leukodystrophy and their relatives

Mol Genet Metab Rep. 2020 Dec 11:25:100688. doi: 10.1016/j.ymgmr.2020.100688. eCollection 2020 Dec.

Affiliations

¹ Department of Medical Biochemistry, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey.
² Department of Pediatric Neurology, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey.
³ Department of Neurology, Neuromuscular Diseases Research Laboratory, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey.
⁴ Department of Medical Genetics, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey.
⁵ Department of Biostatistics, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey.
⁶ Department of Radiology, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey.

Abstract

Metachromatic leukodystrophy (MLD) is a glycosphingolipid storage disease caused by deficiency of the lysosomal enzyme arylsulfatase A (ASA) or its activator protein saposin B. MLD can affect all age groups in severity varying from a severe fatal form to milder adult onset forms. Diagnosis is usually made by measuring leukocyte ASA activity. However, this test can give false negative or false positive laboratory results due to pseudodeficiency of ASA and saposin B deficiency, respectively. Therefore, we aimed to evaluate patients with suspected MLD in a Turkish population by comprehensive clinical, biochemical, radiological, and genetic analyses for molecular and phenotypic characterization. We analyzed 28 suspected MLD patients and 41 relatives from 24 families. ASA activity was found to be decreased in 21 of 28 patients. Sixteen patients were diagnosed as MLD (11 late infantile, 2 juvenile and 3 adult types), 2 MSD, 2 pseudodeficiency (PD) and the remaining 8 patients were diagnosed as having other leukodystrophies. Enzyme analysis showed that the age of onset of MLD did not correlate with residual ASA activity. Sequence analysis showed 11 mutations in ARSA, of which 4 were novel (p.Trp195GlyfsTer5, p.Gly298Asp, p.Arg301Leu, and p.Gly311Asp), and 2 mutations in SUMF1 causing multiple sulfatase deficiency, and confirmed the diagnosis of MLD in 2 presymptomatic relatives. All individuals with confirmed mutations had low ASA activity and urinary sulfatide excretion. Intra- and inter-familial variability was high for the same ARSA missense genotypes, indicating the contribution of other factors to disease expression. Imaging findings were evaluated through a modified brain MRI scoring system which indicated patients with protein-truncating mutations had more severe MRI findings and late-infantile disease onset. MRI findings were not specific for the diagnosis. Anti-sulfatide IgM was similar to control subjects, and IgG, elevated in multiple sulfatase deficiency. In conclusion, the knowledge on the biochemical, clinical and genetic basis of MLD was expanded, a modified diagnostic laboratory algorithm for MLD based on integrated evaluation of ASA activity, urinary sulfatide excretion and genetic tests was devised.

Keywords: ARSA; Antibody; Arylsulfatase A; MRI; Metachromatic leukodystrophy; Multiple sulfatase deficiency; SUMF1; Urinary sulfatide.