Quantitative oculomotor and nonmotor assessments in late-onset GM2 gangliosidosis

Abstract

ObjectiveA cross-sectional study was performed to evaluate whether quantitative oculomotor measures correlate with disease severity in late-onset GM2 gangliosidosis (LOGG) and assess cognition and sleep as potential early nonmotor features.MethodsTen patients with LOGG underwent quantitative oculomotor recordings, including measurements of the angular vestibulo-ocular reflex (VOR), with results compared to age- and sex-matched controls. Disease severity was assessed by ataxia rating scales. Cognitive/neuropsychiatric features were assessed by the cerebellar cognitive affective syndrome (CCAS) scale, Cerebellar Neuropsychiatric Rating Scale, and sleep quality evaluated using subjective sleep scales.ResultsOculomotor abnormalities were found in all participants, including 3/10 with clinically normal eye movements. Abnormalities involved impaired saccadic accuracy (5/10), abnormal vertical (8/10) and horizontal (4/10) pursuit, reduced optokinetic nystagmus (OKN) responses (7/10), low VOR gain (10/10), and impaired VOR cancellation (2/10). Compared to controls, the LOGG group showed significant differences in saccade, VOR, OKN, and visually enhanced VOR gains. Severity of saccadic dysmetria, OKN, and VOR fixation-suppression impairments correlated with ataxia scales (p < 0.05). Nine out of ten patients with LOGG had evidence of the CCAS (5/10 definite, 2/10 probable, 2/10 possible). Excessive daytime sleepiness was present in 4/10 and 8/10 had poor subjective sleep quality.ConclusionsCerebellar oculomotor abnormalities were present in all patients with LOGG, including those with normal clinical oculomotor examinations. Saccade accuracy (dorsal cerebellar vermis localization), fixation suppression, and OKN gain (cerebellar flocculus/paraflocculus localization) correlated with disease severity, suggesting that quantitative oculomotor measurements could be used to track disease progression. We found evidence of the CCAS, suggesting that cerebellar dysfunction may explain the cognitive disorder in LOGG. Sleep impairments were prevalent and require further study.

The cerebellar cognitive affective syndrome scale reveals early neuropsychological deficits in SCA3 patients

“…Similar to a recent study involving nineteen Belgian individuals with Friedreich ataxia, all SCA3 mutation carriers failed at least one CCAS-S item [ 38 ]. The high sensitivity of the CCAS-S to detect cognitive impairment in cerebellar diseases was further supported by an evaluation of ten individuals with late-onset GM2 gangliosidosis [ 39 ]. Whereas subjective cognitive complaints had been reported by only one patient or caregiver, five out of ten met criteria for definite CCAS, two for probable CCAS, and two for possible CCAS, sometimes even in the absence of brain MRI abnormalities.…”

The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment

“…In fact, it is not uncommon to uncover cerebellar symptoms and imaging evidence of cerebellar atrophy at the time of LOTS’s diagnosis regardless of the presenting symptoms. The combination of cerebellar signs and symptoms including mild dysmetria, eye movement abnormalities [ 30 – 32 ], cerebellar dysarthria [ 32 – 34 ], subtle long tract findings and lower extremity weakness may be easily mistaken for one of the spinocerebellar ataxias [ 35 ] ( Table 1 ), In contrast to infantile GM2 gangliosidoses, the presence of a cherry red macula on fundoscopic exam of an adult with ataxia and myoclonus is highly suggestive of an alternate diagnosis of sialidosis type-I or galactosialidosis not LOTS or LOSD. Amongst symptoms related to cerebellar dysfunction, none seem as disabling as the progressive dysarthria of patients with LOTS including characteristic cerebellar features with unique superimposed fast pace, pressured, stuttering and/or explosive quality, that progressively impacts communicative abilities [ 32 – 34 ].…”

“…There is debate as to the degree to which cerebellar atrophy and cerebellar dysfunction, including dysarthria, might be more prevalent and severe in LOTS as compared to LOSD. These differences could result in cases with distinct cerebellar syndromes in LOTS and distinct neuromuscular phenotypes in LOSD [ 29 , 30 , 36 ].…”

Adult-onset non-5q proximal spinal muscular atrophy: a comprehensive review

“…Its major representative ethnic group of patients is from Japan ( from Kansai and Okinawa region), South Korea, Taiwan, and Brazilian patients from Japanese ancestry. Allelic conditions include autosomal recessive hereditary spastic paraplegia type 57 (SPG57) and extraskeletal myxoid chondrosarcoma 43,44,45,46 .…”