Progressive Neurodegeneration in Children: Are We Diagnosing Too Late?

Using metachromatic leukodystrophy (MLD) and Sanfilippo syndrome (mucopolysaccharidosis type 3) as two model diseases, this webinar examines why progressive neurodegenerative disorders in children are so often diagnosed after the point at which treatment can meaningfully change the disease course.

Prof. Samuel Gröschel opens by reviewing the clinical burden of diagnostic delay in MLD, citing survey data in which half of late-infantile patients were already wheelchair-bound and tube-fed by the time of diagnosis, and outcome data from gene therapy and stem cell transplantation showing consistently better results the earlier treatment begins, ideally pre-symptomatically. He covers Germany and Austria's newborn screening pilot (over 350,000 newborns screened, nine true positives identified with no false positives to date) and the practical and ethical challenges of pre-symptomatic diagnosis, including the need for better biomarkers, standardized care for "patients in waiting," and psychological support for families, noting that most affected families support newborn screening even without guaranteed treatment.

Prof. Nicole Wolf then focuses on clinical vigilance in settings without newborn screening, describing underrecognized presentations of MLD, including demyelinating polyneuropathy misdiagnosed as CIDP, new-onset autism or depression in a previously typical child, sudden strabismus, and gallbladder polyps or stones, and shows MRI cases where imaging is initially normal or minimally abnormal despite clear neurological symptoms, sometimes progressing to a fully abnormal scan within months. She presents a detailed case of a five-year-old girl whose tremor and mild gait changes were initially treated as benign, and who progressed to symptomatic early juvenile MLD with an IQ just below the 85-point treatment eligibility threshold, contrasting this with her younger, pre-symptomatic sister who was still eligible for gene therapy.

Dr. Serena Gasperini covers the multisystem presentation of Sanfilippo syndrome, its neuropathology, the range of dysmorphic and behavioral red flags (coarse facial features, macrocephaly, sleep disturbance, recurrent infections, hepatomegaly), the diagnostic role of urinary glycosaminoglycan testing, and current and emerging treatment trials. The session closes with a Q&A covering neurofilament light chain thresholds for treatment eligibility, when to escalate to a specialist center rather than wait for whole exome sequencing results, and red flags that should prompt metabolic testing in children presenting with apparent autism or ADHD.