Modified Delphi procedure-based expert consensus on endpoints for an international disease registry for Metachromatic Leukodystrophy: The European Metachromatic Leukodystrophy initiative (MLDi)

Abstract

Background Metachromatic Leukodystrophy (MLD) is a rare lysosomal disorder. Patients suffer from relentless neurological deterioration leading to premature death. Recently, new treatment modalities, including gene therapy and enzyme replacement therapy, have been developed. Those advances increase the need for high-quality research infrastructure to adequately compare treatments, execute post-marketing surveillance, and perform health technology assessments (HTA). To facilitate this, a group of MLD experts started the MLD initiative (MLDi) and initiated an academia-led European MLD registry: the MLDi. An expert-based consensus procedure, namely a modified Delphi procedure, was used to determine the data elements required to answer academic, regulatory, and HTA research questions. Results Three distinct sets of data elements were defined by the 13-member expert panel. The minimal set (n = 13) contained demographics and basic disease characteristics. The core set (n = 55) included functional status scores in terms of motor, manual, speech and eating abilities, and causal and supportive treatment characteristics. Health-related quality of life scores were included that were also deemed necessary for HTA. The optional set (n = 31) contained additional clinical aspects, such as findings at neurological examination, detailed motor function, presence of peripheral neuropathy, gall bladder involvement and micturition. Conclusion Using a modified Delphi procedure with physicians from the main expert centers, consensus was reached on a core set of data that can be collected retrospectively and prospectively. With this consensus-based approach, an important step towards harmonization was made. This unique dataset will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments.

Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

“…Baseline patient and disease characteristics were collected. According to the age of symptom onset, patients were grouped into late‐infantile, early‐juvenile, late‐juvenile, and adult onset 2 . The patients were categorized into pre‐symptomatic disease, defined as having no symptoms at all, and symptomatic disease.…”

“…According to the age of symptom onset, patients were grouped into late‐infantile, early‐juvenile, late‐juvenile, and adult onset. 2 The patients were categorized into pre‐symptomatic disease, defined as having no symptoms at all, and symptomatic disease. For all symptomatic patients, the phenotype was classified twofold as (1) having a motor, cognitive, or mixed phenotype, as we suggested earlier 5 , 6 and (2) having a CNS or PNS dominant phenotype.…”

“…Its estimated incidence is 1:40.000 births, making it one of the most prevalent leukodystrophies 1 . Based on the age of clinical manifestation, four different types of MLD can be identified: late‐infantile (<2.5 years), early‐juvenile (2.5–6 years), late‐juvenile (6–16 years), and adult MLD (>16 years) 2 . Biallelic pathogenic variants in ARSA or, in rare cases, PSAP result in decreased activity of arylsulfatase A, 3,4 an enzyme crucial for the lysosomal degradation of sulfatides.…”

“…1 Based on the age of clinical manifestation, four different types of MLD can be identified: late‐infantile (<2.5 years), early‐juvenile (2.5–6 years), late‐juvenile (6–16 years), and adult MLD (>16 years). 2 Biallelic pathogenic variants in ARSA or, in rare cases, PSAP result in decreased activity of arylsulfatase A, 3 , 4 an enzyme crucial for the lysosomal degradation of sulfatides. Consequently, sulfatides accumulate, particularly in membranes, which leads to demyelination.…”

Development and pilot implementation of Iranian Hemolytic Uremic Syndrome Registry

“…Then, we conducted a Delphi study to reach a consensus on the HUS registry requirements. Delphi is a popular method to reach a consensus on disease registries [26,27]. Finally, we developed and implemented the registry software.…”