Timely diagnosis of early-onset forms of metachromatic leukodystrophy: an Italian consensus study

Metachromatic leukodystrophy (MLD) is an inherited neurodegenerative disease caused by mutations in the arylsulfatase A (ARSA) gene, leading to progressive demyelination of the central and peripheral nervous systems. Early-onset forms (≤ 7 years) are associated with rapid motor and cognitive decline and reduced survival. Since currently available treatments, such as gene therapy, are effective only when administered at an early stage (preferably before symptom onset), timely diagnosis is crucial. However, early MLD may resemble many neurodegenerative and neurometabolic disorders. Therefore, accurate diagnosis requires a multidisciplinary approach including clinical evaluation, MRI, neurophysiological assessment, biochemical testing, and genetic analysis. Furthermore, newborn screening (NBS) would facilitate the identification of presymptomatic patients but has not yet been fully adopted in Italy (except in the Tuscany and Umbria regions). Considering these challenges, a consensus study aimed at developing an integrated diagnostic protocol was conducted in Italy. The Nominal Group Technique consensus methodology was used. Eight experts from five Italian referral centers contributed to developing and voting (5-point Likert scale) on a series of evidence- and clinically based statements related to six areas: (A) Clinical suspicion and initial assessments; (B) Signs and symptoms suggestive of MLD; (C) Parallel diagnostic approach; (D) Key tests for MLD diagnosis; (E) Family and newborn screening; (F) Identification of referral centers. Consensus was defined as ≥ 66.6% agreement on scores of 4 or 5. Out of 79 statements, 75 reached consensus (71.4–100% agreement); 4 obtained 50% agreement. The highest levels of consensus were achieved for statements regarding signs suggestive of MLD, recommended instrumental exams in case of suspicion, the importance of biochemical and genetic tests for diagnostic confirmation, family screening, and the roles of NBS and referral centers. The high degree of consensus highlights a shared approach to MLD identification in Italy, aimed at ensuring early diaganosis and treatment. Key operational priorities emerged, including the adoption of a standardized diagnostic pathway, the implementation of an NBS program in Italy, and the creation of a national network of reference centers and qualified laboratories.