The clinical utility of neurofilament light chain for early detection and prediction of disease burden and severity in neuronopathic Gaucher disease.

Newborn screening, while enabling early diagnosis, poses challenges to correctly identifying and typing otherwise asymptomatic infants with neuropathic Gaucher disease (nGD). Glucosylsphingosine (Lyso-GL1) may be elevated at birth, but it does not help differentiate between nGD types. Neurofilament light chain (NfL), a neuronal cytoplasmic protein, is a marker for axonal damage and is associated with elevated levels in cerebrospinal fluid (CSF) and blood in lysosomal disorders characterized by neurodegeneration. In a prospective study (NCT02000310, 13-CFCT-07), NfL and Lyso-GL1 levels were assessed along with other neurological indicators in 35 GD patients (ages 6 months to 72 years: 8 GD1, 7 GD2, 20 GD3). Eighteen patients with other LSDs-with or without neurodegeneration-served as controls. In GD2, Lyso-GL1 was markedly elevated (range: 105-457 ng/mL), and all GD2 patients with neurological manifestations had elevated NfL. In GD3, Lyso-GL1 levels were highly variable, reflecting the clinical heterogeneity. NfL was elevated in 4 of 20 GD3 patients, all of whom had clinically discernable neurological involvement. All GD1 patients had normal NfL levels (max: 0.9 (ref:<1.63)) and near-normal Lyso-GL1 (maximum pretreatment: 10). Clinically, an abnormal Auditory Brainstem Response (ABR) correlated with neurodegeneration. ABR was abnormal in all GD2 infants tested, while 65 % (13/20) of GD3 patients had normal auditory function. The combination of elevated NfL and Lyso-GL1 levels, along with abnormal ABR, can aid in the early identification of severe nGD-even in the absence of characteristic neurological symptoms-supporting the need for earlier diagnosis and timely clinical intervention.