An Introduction And Overview Of Metachromatic Leukodystrophy (MLD) In Children

MLD is a rare lysosomal storage disorder caused by a deficiency in the enzyme arylsulfatase A (ASA), resulting in the accumulation of sulfatides in myelin-rich tissues of the central and peripheral nervous systems. The condition is autosomal recessive and can lead to progressive neurological deterioration. Diagnosis typically involves clinical assessment, MRI findings, ASA enzyme activity measurement in leukocytes, sulfatide excretion in urine, and genetic analysis.

MLD presents in three clinical forms: late infantile (onset <30 months), juvenile (30 months–16 years), and adult (>16 years). Early-onset cases often show motor regression and rapid progression, while later-onset forms are more associated with cognitive decline and slower progression. Dr. Wolf emphasizes that early signs can be subtle and are often mistaken for more common developmental or behavioral issues, such as ADHD, autism, or learning difficulties. Common misdiagnoses include chronic inflammatory demyelinating polyneuropathy (CIDP), particularly when high cerebrospinal fluid (CSF) protein and peripheral neuropathy are observed.

MRI plays a central role in diagnosis, with characteristic patterns such as the "tigroid" appearance of the white matter and specific involvement of the corpus callosum. However, early MRI findings can be subtle and easily overlooked. The presence of strabismus, clumsiness, developmental regression, or unexplained school difficulties should raise suspicion, particularly when new symptoms emerge in a previously well child.

Treatment options include hematopoietic stem cell transplantation (HSCT) and ex vivo gene therapy, which are only effective in pre-symptomatic or very early stages of disease. Therefore, early diagnosis is critical—not only to initiate treatment but also for family genetic counseling and pre-symptomatic testing of siblings. Dr. Wolf highlights the importance of newborn screening programs, which are being piloted in countries like Italy and the United States.

The session concludes with a Q&A segment, addressing practical diagnostic challenges and emphasizing the need for awareness among pediatricians to recognize early red flags. Dr. Wolf encourages clinicians to refer suspected cases to specialist centers and consider MLD as a differential diagnosis in children presenting with unexplained neurodevelopmental regression or motor decline.