Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra-rare disease

Laura A Adang, Lars Schlotawa, Samuel Groeschel, Christiane Kehrer, Klaus Harzer, Orna Staretz-Chacham, Thiago Oliveira Silva, Ida Vanessa D Schwartz, Jutta Gärtner, Mauricio De Castro, Carrie Costin, Esperanza Font Montgomery, Thomas Dierks, Karthikeyan Radhakrishnan, Rebecca C Ahrens-Nicklas, Laura A Adang, Lars Schlotawa, Samuel Groeschel, Christiane Kehrer, Klaus Harzer, Orna Staretz-Chacham, Thiago Oliveira Silva, Ida Vanessa D Schwartz, Jutta Gärtner, Mauricio De Castro, Carrie Costin, Esperanza Font Montgomery, Thomas Dierks, Karthikeyan Radhakrishnan, Rebecca C Ahrens-Nicklas

Abstract

Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine-generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype-phenotype relationship and detailed clinical course is unknown. We report on 35 cases enrolled in our retrospective natural history study, n = 32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel SUMF1 variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score. The median age at symptom onset was 0.25 years; median age at diagnosis was 2.7 years; and median age at death was 13 years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden. Earlier age at symptom onset and severe variant pathogenicity correlated with poor neurologic outcomes. Using retrospective deep phenotyping and detailed variant analysis, we defined the natural history of MSD. We found that attenuated cases can be distinguished from severe cases by age of onset, attainment of ambulation, and genotype. Results from this study can help inform prognosis and facilitate future study design.

Trial registration: ClinicalTrials.gov NCT03047369.

Keywords: leukodystrophy; mucopolysaccharidoses; multiple sulfatase deficiency; outcomes.

Conflict of interest statement

Laura Adang: MLD Foundation and CureMLD scientific advisory board member. Rebecca Ahrens‐Nicklas and Lars Schlotawa: Medical advisors to the United MSD Foundation. Mauricio De Castro: Board of Directors United MSD Foundation. Samuel Groeschel, Christiane Kehrer, Klaus Harzer, Orna Staretz‐Chacham, Thiago Oliveira Silva, Ida Vanessa D. Schwartz, Jutta Gärtner, Carrie Costin, Esperanza Font Montgomery, Thomas Dierks, Karthikeyan Radhakrishnan declare they have no conflicts of interest.

© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Figures

FIGURE 1
FIGURE 1
Survival and age at clinical onset and diagnosis in MSD. A, Overall survival within the MSD cohort presented by Kaplan‐Meier curve with 95% confidence interval (shaded). B, Paired age at clinical onset and age at diagnosis were available for 27 individuals, presented as a swim lane plot. Each individual is represented by a horizontal bar beginning at the age at presentation and ending at diagnosis
FIGURE 2
FIGURE 2
Key time to event measures and clinical features in MSD. A, Key disease‐specific clinical outcomes, and B, C, exam features were collected in the medical records as available. Events or features were classified as either yes (event/feature noted at any point in the medical record; dark blue) or no (event/feature noted not to have occurred; light blue). The total number of records with available information is noted on the left y‐axis. For medical complications (time to event measures), the mean age (± SE of the mean) at which the first event occurred is shown (right axis, black circles)
FIGURE 3
FIGURE 3
Developmental heat maps in MSD. For each available medical encounter, gross motor, fine motor, and language skills were retrospectively classified using the GMFC‐MLD, MACS, and ELFC, respectively
FIGURE 4
FIGURE 4
Gross motor, swallowing and expressive language function in MSD. A, Gross motor function was scored at each available medical encounter using the GMFC‐MLD in 29 individuals. Score corresponds to function as follows: 0 = walking without support; 1 = walking without support reduced quality of performance; 2 = walking with support; 3 = sitting without support AND crawling/rolling; 4 = either sitting without support OR crawling/rolling; 5 = no sitting without support AND no crawling/rolling; 6 = no head or trunk control. B, Swallowing function was scored at each available medical encounter using the EDACS in 26 individuals. Score corresponds to function as follows: 0 = eats and drinks safely and efficiently; 1 = some limitations to efficiency; 2 = some limitations to safety; 3 = significant limitations to safety; 4 = unable to eat or drink safely. C, Expressive language was scored at each available medical encounter using the ELFC‐MLD in 29 individuals. Score corresponds to function as follows: 0 = speaks in complete sentences of normal quality; 1 = speaks in complete sentences of reduced quality; 2 = speaks in maximum of 2‐word phrases; 3 = speaks in single words; 4 = complete loss of expressive language. Individuals who never attained independent ambulation are noted with red, dotted lines, while those who were able to independently ambulate are noted in solid blue lines
FIGURE 5
FIGURE 5
In vitro residual sulfatase activity and FGE stability of novel SUMF1 variants. A, Steroid sulfatase (STS) and arylsulfatase A (ARSA) activities were measured in cells harboring each of the 9 novel SUMF1 variants. Bar diagram depicting the comparison of the specific activity of STS and ARSA relative to activity of cells expressing FGE‐WT (Also see Figure S1). The values represent mean ± SEM of three independent experiments. B, The stability of the novel FGE variants was compared to wildtype and the half‐life (t1/2) was calculated (see legend). Plot depicts the percentage of FGE remaining after cycloheximide chase for the indicated time points. The amount of FGE was determined by quantification of signals corresponding of FGE in western blots (see Figure S2). After normalization of the anti‐HA antibody signals (corresponding to FGE) in cell lysates to anti‐Hsc70 signals, the total amount of FGE (μg/mg of total protein in lysate) in the cells and media were combined and expressed as the percentage of that at the start of the chase (0 hours)
FIGURE 6
FIGURE 6
Relationship between clinical biochemical testing and genotypic severity in MSD. A, For each individual with at least two documented sulfatase activity results, genotype severity score, residual enzyme activity, and glycosaminoglycan (GAG) results are shown. B, There is no significant correlation between residual ARSA activity in blood and age at onset of motor regression (ie, last age at best GMFC‐MLD score before regression)
FIGURE 7
FIGURE 7
Early features that correlate with outcomes in MSD. A, Venn diagram showing the overlap between subjects presenting in the neonatal period (= 6), subjects presenting after the neonatal period (>1 mo, dark blue, n = 14), and subjects with attenuated genotypes (light blue, n = 17). The cohort was divided by age of onset before or after 1 month, and the number of subjects that attained, B, independent ambulation, and C, multiword speech are shown (chi‐square test, P values as labeled). D, Freedom from regression divided by age of onset is shown (log‐rank Mantel‐Cox test, P = .0005). E, Survival divided by age of onset is shown (log‐rank Mantel‐Cox test, P = .016). The cohort was also divided by genotype severity (attenuated = score of 2‐3, severe = score of 4), and the number of subjects that attained (F) independent ambulation, and G, multiword speech are shown (chi‐square test, P values as labeled). Freedom from regression divided by genotype severity is shown (log‐rank Mantel‐Cox test, P < .0001). Neurologic regression (H) and survival (I) are presented by Kaplan‐Meier curves, with subcohorts defined by genotype severity (log‐rank Mantel‐Cox test, P < .0001 and P = .047, respectively)

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