Adult-onset Sandhoff disease presenting with a motor neuron disease phenotype: clinical and mechanistic insights from patient-derived models.

Sandhoff disease (SD) is a subtype of GM2 gangliosidosis caused by pathogenic variants in Hexosaminidase B (HEXB). It most frequently presents in infancy or early childhood, whereas adult-onset disease is rare and remains incompletely characterized. Here, we describe an adult-onset case of SD presenting as motor neuron disease and provide clinical and mechanistic insights using patient-derived models. The patient was a 34-year-old man with compound heterozygous HEXB variants (c.1598G > A, p.Arg533His and c.1645G > A, p.Gly549Arg) who developed progressive lower limb weakness. Muscle biopsy demonstrated neurogenic changes consistent with denervation, and sural nerve biopsy revealed mild peripheral neuropathy. Nerve conduction studies and electromyography showed widespread neurogenic changes with mildly reduced sensory nerve action potential amplitudes, and leukocyte β-hexosaminidase activity was decreased. To investigate disease mechanisms, we generated induced pluripotent stem cells (iPSCs) from the patient and an isogenic CRISPR-Cas9-corrected control (ISO), and differentiated both lines into motor neurons (MNs). In the SD patient (SDHF)-derived MNs, we observed lysosomal expansion, increased apoptosis, reduced neuronal network excitability, and dysregulated lipidomic profiles. These phenotypes were attenuated in MNs derived from the ISO line, with multiple measures shifting toward those of control (CTL) MNs. Collectively, our findings expand the clinical spectrum of adult-onset SD and support an association between HEXB deficiency and the vulnerability of MNs, while underscoring the value of patient-derived iPSC models for mechanistic studies of lateonset SD.