Extremely low arylsulfatase A enzyme activity does not necessarily cause symptoms: A long-term follow-up and review of the literature

Abstract

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.

Keywords: ARSA; ARSA pseudodeficiency; MLD; MRI; arylsulfatase A; newborn screening.

FIGURE 1

MRI data. Cerebral T2‐weighted MRI of the index case at the age of 59 years (A) with no signs of demyelination, which is comparable to that of a healthy adult control (B). In contrast, T2‐weighted MRI of a patient with adult onset of MLD (C) and juvenile onset of MLD (D) reveal marked demyelination

FIGURE 2

Arylsulfatase A (ARSA) enzyme activity in different cohorts. The ARSA activity is indicated as nmol/h/10⁶ cells. Lower limit, indicated by the dashed line, was set as 0.33 nmol/h/10⁶ cells (26% of mean control activity). The activity of the control cohort was 1.26 ± 0.33 nmol/h/10⁶cells (n = 67). With 1.6% of mean control activity, ARSA activities were significantly lower in MLD patients (mean 0.02 ± 0.02 nmol/h/10⁶cells; n = 72 [p < 0.0001]). Heterozygotes show 40.2% of mean control activity (mean 0.51 ± 0.19 nmol/h/10⁶cells; n = 30). The index case 1 revealed an enzyme activity of 7.8% (0.098 nmol/h/10⁶cells) (labelled in red) and index 2 5.2% (0.066 nmol/h/10⁶cells) (labelled in red) compared to mean control activity, which is in the range of the PD cohort (mean 0.10 ± 0.02 nmol/h/10⁶cells; n = 4). All cohorts differed significantly based on Mann–Whitney test (p < 0.0001). Whiskers at 10–90 percentiles