Open AccessExtremely low arylsulfatase A enzyme activity does not necessarily cause symptoms: A long‐term follow‐up and review of the literature
Author(s) -
Laugwitz Lucia,
Santhanakumaran Vidiyaah,
Spieker Mareike,
Boehringer Judith,
Bender Benjamin,
Gieselmann Volkmar,
BeckWoedl Stefanie,
Bruchelt Gernot,
Harzer Klaus,
KraegelohMann Ingeborg,
Groeschel Samuel
Publication year - 2022
Publication title -
jimd reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.412
H-Index - 25
ISSN - 2192-8312
DOI - 10.1002/jmd2.12293
Subject(s) - arylsulfatase a , metachromatic leukodystrophy , compound heterozygosity , context (archaeology) , allele , leukodystrophy , genotype , heterozygote advantage , medicine , lysosomal storage disease , disease , gastroenterology , biology , pathology , gene , genetics , paleontology
Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency of arylsulfatase A (ARSA). Heterozygous carriers of disease‐causing variants and individuals harbouring pseudodeficiency alleles in the ARSA gene exhibit reduced ARSA activity. In the context of these genotypes, low ARSA activity has been suggested to lead to an atypical form of MLD or other neurological abnormalities, but data are limited. The aim of our study was to analyse the impact of low ARSA activity in two subjects who are heterozygous for the ARSA pseudodeficiency allele and a disease‐causing variant. Biochemical testing included ARSA activity measurements and urinary sulfatide analysis. Biochemical data of a large cohort of MLD patients, heterozygotes, pseudodeficient individuals and healthy controls were analysed. MRI was performed at 3T using T1‐ and T2‐weighted sequences and MR spectroscopy. We present two long‐term follow‐ups who are heterozygous for the ARSA pseudodeficiency allele and a disease‐causing variant in the ARSA gene in cis. The two related index cases exhibit markedly reduced ARSA activity compared to controls and heterozygous carriers. The neurological evaluation and MRI do not reveal any abnormalities. Our data underline that extremely low enzyme activity due to a pseudodeficiency allele and a disease‐causing variant in the ARSA gene even in cis does not lead to clinical symptoms or pre‐symptomatic MRI changes suspicious for MLD. The review of literature corroborates that any association of low ARSA activity with disease features remains questionable. It seems important to combine the measurement of ARSA activity with elevated sulfatide as well as genetic testing, as done in current newborn screening approaches. Heterozygosity for metachromatic leukodystrophy and an arylsulfatase A pseudodeficiency allele does not cause neurological or neuropsychiatric features.