Clinical and imaging predictors of late-onset GM2 gangliosidosis: A scoping review

Abstract

Objective: Late-onset GM2 gangliosidosis (LOGG) subtypes late-onset Tay-Sachs (LOTS) and Sandhoff disease (LOSD) are ultra-rare neurodegenerative lysosomal storage disorders presenting with weakness, ataxia, and neuropsychiatric symptoms. Previous studies considered LOTS and LOSD clinically indistinguishable; recent studies have challenged this. We performed a scoping review to ascertain whether imaging and clinical features may differentiate these diseases.

Methods: We examined MEDLINE/non-MEDLINE databases up to May 2022. Articles reporting brain imaging findings in genetically/enzymatically confirmed LOGG, symptom onset at age ≥ 10 years (or evaluated at least once ≥18 years) were included, yielding 170 LOGG patients (LOTS = 127, LOSD = 43) across 68 papers. We compared LOTS versus LOSD and performed regression analyses. Results were corrected for multiple comparisons.

Results: Age of onset was lower in LOTS versus LOSD (17.9 ± 8.2 vs. 23.9 ± 14.4 years, p = 0.017), although disease duration was similar (p = 0.34). LOTS more commonly had psychosis/bipolar symptoms (35.0% vs. 9.30%, p = 0.011) but less frequent swallowing problems (4.10% vs. 18.60%, p = 0.041). Cerebellar atrophy was more common in LOTS (89.0%) versus LOSD (60.5%), p < 0.0001, with more severe atrophy in LOTS (p = 0.0005). Brainstem atrophy was documented only in LOTS (14.2%). Independent predictors of LOTS versus LOSD (odds ratio [95% confidence interval]) included the presence of psychosis/bipolar symptoms (4.95 [1.59-19.52], p = 0.011), no swallowing symptoms (0.16 [0.036-0.64], p = 0.011), and cerebellar atrophy (5.81 [2.10-17.08], p = 0.0009). Lower age of onset (0.96 [0.93-1.00], p = 0.075) and tremor (2.50 [0.94-7.43], p = 0.078) were marginally statistically significant but felt relevant to include in the model.

Interpretation: These data suggest significant differences in symptomatology, disease course, and imaging findings between LOTS and LOSD.

Figure 1

PRISMA flowchart for scoping review in the LOGG cohort.

Figure 2

Clinical characteristics of LOGG, LOTS, and LOSD and by age of onset subgroups. Bar graphs illustrate differences in clinical characteristics comparing LOTS to LOSD (2A); with comparison in young (<18 years) and late (≥18 years) onset subgroups in LOGG (2B), LOTS (2C), and LOSD (2D). Significance label * indicates p < 0.05. LMN: lower motor neuron clinical signs; UMN: upper motor neuron clinical signs; cognitive: cognitive symptoms/signs; psychiatric: psychosis/bipolar symptoms; speech: speech disturbance; swallow: swallowing symptoms/dysfunction.

Figure 3

Clinical characteristics of LOTS, and LOSD by ataxia, psychiatric, and cognitive symptoms. Bar graphs illustrate differences in clinical characteristics comparing LOTS to LOSD in the main phenotypes: (A) ataxic versus non‐ataxic (neuromuscular) phenotypes; (B) psychiatric versus nonpsychiatric phenotype; (C) cognitive disorder versus normal cognition phenotypes. Significance labels: * indicates p < 0.05, ** p < 0.01. LMN: lower motor neuron clinical signs; UMN: upper motor neuron clinical signs; cognitive: cognitive symptoms/signs; psychiatric: psychosis/bipolar symptoms; speech: speech disturbance; swallow: swallowing symptoms/dysfunction.

Figure 4

Imaging findings in LOTS and LOSD by main clinical phenotypes and clinical differences in the setting of cerebellar atrophy. Bar graphs highlight differences in imaging findings, including the presence of cerebellar, brainstem and cerebral atrophy across the main phenotypes: (A) ataxic versus non‐ataxic (neuromuscular) phenotypes; (B) psychiatric versus nonpsychiatric phenotype; (C) cognitive disorder versus normal cognition phenotypes. (D) illustrates differences in clinical characteristics in LOTS/LOSD subgroups with either the presence or absence of a description of cerebellar atrophy on imaging. Significance labels: * indicates p < 0.05, ** p < 0.01. LMN: lower motor neuron clinical signs; UMN: upper motor neuron clinical signs; cognitive: cognitive symptoms/signs; psychiatric: psychosis/bipolar symptoms; speech: speech disturbance; swallow: swallowing symptoms/dysfunction; CA: cerebellar atrophy; psych: psychiatric phenotype.

Figure 5

Clinical and imaging predictors of LOTS versus LOSD. This pertains to the final logistic regression model predicting LOTS versus LOSD: (A) the comparative odds ratios (OR) of LOTS relative to LOSD and 95% confidence intervals for the 5 predictors (age of onset in whole years, psychosis/bipolar symptoms, swallowing symptoms, tremor, and the presence of cerebellar atrophy on imaging); (B) the receiver operating characteristic (ROC) curve of the final model for prediction of a diagnosis of LOTS; (C) the relative predicted probabilities of LOTS depending on differing ages of onset with or without psychosis/bipolar symptoms, swallowing problems or tremor, in the absence of cerebellar atrophy on imaging, and (D) the presence of cerebellar atrophy on imaging. swallow Sx: swallowing symptoms/dysfunction; yr: years of age.