Insights into the natural history of metachromatic leukodystrophy from interviews with caregivers

Abstract

Background and methods Metachromatic leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disease caused by deficient activity of arylsulfatase A. Neurological involvement results in severe disability and premature death, but understanding of the natural history of the disease remains limited. In this study, 32 caregivers of patients with MLD in the USA (16 with late-infantile MLD; 16 with juvenile MLD) were interviewed about their experiences of the disease. Qualitative analysis of the interview transcripts was performed to gain insights into symptom onset, the diagnostic process and disease progression, with a focus on the differences between late-infantile and juvenile MLD. Results The mean ages of patients at interview were 7.6 years and 20.7 years for individuals with late-infantile and juvenile MLD, respectively. Patients with late-infantile MLD had a mean age of 1.5 years at symptom onset and 2.6 years at diagnosis. The most common initial symptoms in this group related to problems with gross motor function (12/16 patients); 11 patients never learned to walk independently. For patients with juvenile MLD, the mean ages at symptom onset and diagnosis were 8.7 years and 11.6 years, respectively. Cognitive or social/behavioural problems were the most common first reported symptoms in this group (9/16 and 7/16 patients, respectively); these were generally followed by deterioration in motor function. The rate of functional decline was more rapid in patients with late-infantile MLD than those with juvenile MLD; the mean time from first symptom to first functional loss was 1 year versus 6.1 years, respectively. Nine patients with juvenile MLD and three with late-infantile MLD had undergone a haematopoietic stem cell transplant; outcomes following transplant were variable. Conclusions Our data highlight clear overall differences in symptom profiles and disease progression between late-infantile and juvenile MLD, but also indicate some degree of interindividual variability within each subtype. These findings are broadly consistent with previously published descriptions of MLD and enhance our knowledge of the natural history of the disease, which ultimately should help to improve patient care and aid assessments of the effectiveness of disease-related interventions in the future. Electronic supplementary material The online version of this article (10.1186/s13023-019-1060-2) contains supplementary material, which is available to authorized users.

A systematic review and meta‐analysis of published cases reveals the natural disease history in multiple sulfatase deficiency

“…Therefore MSD is no exemption but in line with diseases like Krabbe disease, MLD, MPS IIIA, and free sialic acid storage disease. 26,[29][30][31][32] A classification system for MSD that is capable of prognosticating clinical outcomes should We propose that a disease classification for MSD, allowing predictions of disease severity, should include multiple co-variants like age of onset, number of key clusters of signs, involvement of specific organ systems, and psychomotor development.…”

“…Spectra of disease severity rather than fixed categories have recently been discussed for other lysosomal storage disorders for which actual natural disease history data have been acquired prospectively or from systematic reviews. Therefore MSD is no exemption but in line with diseases like Krabbe disease, MLD, MPS IIIA, and free sialic acid storage disease 26,29‐32 . A classification system for MSD that is capable of prognosticating clinical outcomes should We propose that a disease classification for MSD, allowing predictions of disease severity, should include multiple co‐variants like age of onset, number of key clusters of signs, involvement of specific organ systems, and psychomotor development.…”

Intravenous arylsulfatase A in metachromatic leukodystrophy: a phase 1/2 study

“…For patients with juvenile and adult MLD, cognitive and behavioral symptoms are often observed first, followed by a more protracted decline in motor function 6,7 . These distinctions are not absolute, however, and disease severity may be considered a continuum, with particular overlap between late‐infantile and early‐juvenile presentation 1,8 …”

Caregiver Perspective on The Initial Signs and Symptoms of Metachromatic Leukodystrophy

“…From a caregiver perspective, this time between symptom onset and diagnosis is characterized by uncertainty, frustration, and fear. While there are a few studies focused on MLD that highlight or include a caregiver perspective, there is continued need to better understand caregivers' experiences early in the disease process to enhance our understanding of how to identify MLD more quickly [11,12]. The goal of this paper is to contribute to our understanding of how caregivers describe the initial symptomatology of MLD and ultimately to improve communication between clinicians and families impacted by this condition.…”