Clinical, Biochemical, and Molecular Characterization of Metachromatic Leukodystrophy Among Egyptian Pediatric Patients:
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Clinical, Biochemical, and Molecular Characterization of Metachromatic Leukodystrophy Among Egyptian Pediatric Patients: Expansion of the ARSA Mutational Spectrum Khalda Amr1 · Ekram Fateen2 · Lobna Mansour3 · Angie MS Tosson3 · Maha S. Zaki4 · Ghada MH. Abdel Salam4 · Ahmed Nabil Mohamed5 · Hala T. El‑Bassyouni4 Received: 27 July 2020 / Accepted: 14 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Metachromatic leukodystrophy (MLD) is a neurodegenerative disorder characterized by progressive demyelination due to deficiency of the enzyme arylsulfatase A (ARSA) in leukocytes, and consequently leads to impaired degradation and accumulation of cerebroside-3-sulfate (sulfatide). This study aimed to sequence the ARSA gene in a total of 43 patients with metachromatic leukodystrophy descendant from 40 Egyptian families. In addition, four carrier parents from two families with children who had died from MLD came to the clinic for genetic analysis. Prenatal diagnosis was performed for four families with molecularly diagnosed MLD sibs. Different mutations were characterized in our cohort, including missense, nonsense, splice, and deletion. Overall, 21 different mutations in the ARSA gene were detected, with 12 novel mutations, i.e. p.Arg60Pro, p.Tyr65*, p.Val112Asp, p.Arg116*, p.Gly124Asp, p.Pro193Ser, p.Gln238*, p.Gln456*, p.Thr276Lys, and p.Gly311Arg, in addition to two new acceptor splice-site mutations 685-1G > A and c.954_956 delCTT. The amniotic fluid samples revealed two carrier fetuses with heterozygous monoallelic mutations, and two affected fetuses had the homozygous biallelic mutations. In conclusion, the current study sheds light on the underlying ARSA gene defect, with an expansion of the mutation spectrum. To our knowledge, this is the first molecular study of MLD among the Egyptian population. Keywords Arylsulfatase A · ARSA gene · Magnetic resonance imaging (MRI) brain · Metachromatic leukodystrophy (MLD)
Introduction Metachromatic leukodystrophy (MLD) (MIM #250100) is a severe neurodegenerative disorder inherited as an autosomal recessive trait, with estimated worldwide prevalence of * Hala T. El‑Bassyouni [email protected] 1
Medical Molecular Genetics, National Research Center, Cairo, Egypt
2
Biochemical Genetics Department, National Research Centre, Cairo 12622, Postal Code, Egypt
3
Pediatrics Department, Faculty of Medicine, Kasr Al Ainy, Cairo University, Cairo, Egypt
4
Clinical Genetics Department, National Research Centre, Cairo, Egypt
5
Prenatal Diagnosis and Fetal Medicine Department, National Research Centre, Cairo, Egypt
1.45 per 100,000 births (Giugliani 2012). MLD is caused by deficient activity of the enzyme arylsulfatase A (ARSA) and leads to sulfatide storage within the lysosomes (Cesani et al., 2016). ARSA catalyzes the initial step of the metabolic pathway, sphingolipid 3′-O-sulfogalactosylceramide, known as sulfatide, which accumulates in myelin-producing cells and causes progressive demyelination and neurodegeneration (
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