Late-Onset Tay-Sachs Disease With SMALED-Like Muscle MRI Pattern Despite a Distinct Clinical Phenotype

J Peripher Nerv Syst. 2026 Sep;31(3):e70144. doi: 10.1111/jns.70144.

ABSTRACT

BACKGROUND: Late-onset Tay-Sachs disease (LOTS) is a rare lysosomal disorder that contrasts with the classical infantile form by presenting with milder and heterogeneous neurological manifestations, including lower motor neuron phenotypes. While muscle MRI fatty infiltration patterns have been described in selected inherited motor neuron disorders, the corresponding imaging features in LOTS remain poorly defined.

CASE: We report two female patients presenting in the second decade of life with slowly progressive, lower limb-predominant flaccid weakness associated with tremor. Hip flexion and arm extension were disproportionately affected. Electromyography demonstrated a neurogenic pattern. Whole-body muscle MRI (wbMRI) revealed selective fatty infiltration on T1-weighted sequences with normal STIR imaging. At the pelvic and thigh levels, this pattern showed marked overlap with the characteristic fatty infiltration described in SMA with lower extremity predominance (SMALED), including relative sparing of the adductor longus and semimembranosus. In contrast, consistent additional involvement of the iliopsoas and triceps brachii muscles was observed. Whole-exome sequencing identified compound heterozygous pathogenic variants in the HEXA gene in each patient, confirmed to be in trans, and enzymatic testing demonstrated reduced β-hexosaminidase A activity.

CONCLUSION: LOTS may reproduce key elements of the SMALED muscle MRI fatty infiltration pattern, particularly at the pelvic and thigh levels, while maintaining a distinct clinical presentation. Recognition of this partial radiological overlap, together with its discriminative features, is important to avoid diagnostic misclassification and to guide appropriate genetic testing.

PMID:42466981 | DOI:10.1111/jns.70144