ARSA Variants Associated With Cognitive Decline and Long-Term Preservation of Motor Function in Metachromatic Leukodystrophy

Abstract

Patients with metachromatic leukodystrophy (MLD) show variable motor and cognitive decline. The ARSA variants c.256C>T, p.(Arg86Trp), c.257G>A, p.(Arg86Gln) and c.542T>G, p.(Ile181Ser) are associated with predominantly cognitive decline. This multinational study analyzed MLD onset type, presenting signs/symptoms, cognitive function, gross motor function, central motor tract involvement, MRI severity score, peripheral neuropathy, and survival of 47 patients (three homozygous for c.256C>T and five, twelve and 27 compound heterozygous for c.256C>T, c.257G>A, or c.542T>G and another ARSA variant, respectively). Eleven underwent hematopoietic stem cell transplantation (HSCT). Onset was late-juvenile (46.8%) or adult (44.7%) with predominantly cognitive decline (n = 40/41 symptomatic patients). At diagnosis, untreated patients typically retained independent walking (100%), sparing of central motor tracts (87.5%), and absence of demyelinating neuropathy (95.5%), which persisted in follow-up for most (76.5%, 71.4%, and 64.7%, respectively). Early-juvenile onset and rapid motor decline occurred only in patients compound heterozygous for c.256C>T and a severe second variant (n = 4), showing central motor tract involvement at diagnosis. One untreated and one treated patient died of disease progression, and another from HSCT complications. All other treated patients retained independent walking, and four of five tested normal cognitive function. Median MRI severity score remained lower in treated (13) than untreated patients (25). The phenotype of c.256C>T carriers depends on the severity of the second ARSA variant. Patients harboring c.257G>A or c.542T>G show late-juvenile or adult onset with cognitive decline and preserved motor function, usually associated with sparing of central motor tracts. In these patients, cognitive function and MRI severity score should be preferred treatment outcomes.

Keywords: ARSA gene; arylsulfatase A; genetic association studies; hematopoietic stem cell transplantation; metachromatic leukodystrophy.

FIGURE 1

MRI assessment of central motor tract involvement. Transverse FLAIR images illustrating central motor tract involvement at the posterior limb of the internal capsule (left) and the white matter under the Rolandic area (right). Upper panel: Images from a patient homozygous for the c.256C>T, p.(Arg86Trp) variant with sparing of the central motor tracts, showing nearly normal signal intensity in the white matter of the corticospinal tracts under the Rolandic area at diagnosis at age 30 years (A) and follow‐up (FU) at age 37 years (B), despite surrounding abnormal white matter with increased signal intensity and abnormal signal in the internal capsule. Lower panel: Images from a patient compound heterozygous for c.256C>T, p.(Arg86Trp), and c.465+1G>A, p.(?) without sparing of the central motor tracts, displaying significantly increased signal intensity in the white matter of the corticospinal tracts under the Rolandic area at diagnosis at age 4 years (C) and FU at age 14 years (D), similar to the surrounding abnormal white matter and abnormal internal capsule.

FIGURE 2

Distribution and severity of ARSA variants identified in this study and location of affected amino acid residues. (A) Donut chart illustrating the proportion of patients with MLD onset types within the c.256C>T, p.(Arg86Trp), c.257G>A, p.(Arg86Gln), and c.542T>G, p.(Ile181Ser) groups. The distribution of the second ARSA variants per MLD onset type is shown across these groups. Functional severity of the second ARSA variants is indicated based on Trinidad et al., with known severe variants in red, known mild or moderate variants in black, and variants with unknown functional severity in blue. Asterisks (*) denote conflicting interpretations of functional severity. (B) 3D model of the ASA monomer (Protein Data Bank 1AUK, visualized using the PyMOL Molecular Graphics System, Version 3.0.3 Schrödinger LLC [31]) depicting the locations of amino acid residue Arg86 (blue, affected by the c.256C>T and c.257G>A variants) and Ile181 (yellow, affected by the c.542T>G variant) and three other commonly affected amino acid residues in MLD: Pro428, commonly affected in patients with late‐juvenile and adult MLD, is orange. Gly124 and Gly310, affected in patients with late‐infantile MLD, are red. Amino acid residues forming the active center of ASA are highlighted in teal. Helices, β‐sheets, and loops are represented as ribbons, arrows, and threads, respectively.

FIGURE 3

Overview of presenting signs and symptoms. Black dots represent individual presenting signs and symptoms or combinations of them (multiple black dots connected). The total bar length indicates the total number of patients with each combination. Separate colored bars show the number of patients with each combination per ARSA variant included in the study. Other presenting signs and symptoms were impaired fine motor skills in two patients (one early‐juvenile patient compound heterozygous for c.256C>T, p.(Arg86Trp) and one late‐juvenile patient compound heterozygous for c.257G>A, p.(Arg86Gln), both harboring a severe second variant in trans) and spasticity in one late‐juvenile patient (compound heterozygous for c.257G>A, p.(Arg86Gln) and a severe second variant in trans).

FIGURE 4

Overview of measurements at diagnosis and follow‐up, with separated analysis for untreated and HSCT‐treated patients. (A–C, E, F) Bar graphs show patient counts and percentages by category at diagnosis and follow‐up (FU). Colored lines connect individual patients to their respective categories, while unconnected lines within the red boxes indicate no assessments at diagnosis (NA) and/or FU (NA at FU). X's denote the two patients who died due to HSCT complications (pink) or MLD progression after unsuccessful HSCT due to engraftment failure (orange). (D) Box plots display median and iqr at diagnosis and FU, with dots representing individual patients and lines connecting their measurements at diagnosis and FU. (A) Cognitive function categories: No to borderline impairment (FSIQ ≥ 70), mild impairment (FSIQ 50–69), and severe impairment (FSIQ ≤ 49). (B) Gross Motor Function according to the GMFC‐MLD scale with score 0 indicating normal locomotion and score 6 indicating loss of all gross motor function; no patients scored 4. (C) Central motor tracts sparing: Yes/No, based on whether the white matter of the corticospinal tracts under the Rolandic area was visually “spared” or “not spared”, independent of involvement of the posterior limb of the internal capsule. (D) MLD MRI severity score with score 0 indicating no MRI abnormalities and score 34 most severe MRI abnormalities: The median annual increase in MRI severity score was 1.0 in the untreated group and 0.3 in the treated group. (E) Demyelinating neuropathy and (F) Signs of axonal degeneration on nerve conduction studies and electromyography: Yes/No, according to locally used criteria and reference values.