The Natural History of Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and Literature Review of 134 Previously Reported

Abstract

OBJECTIVE-Juvenile GM2 gangliosidosis is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal β-hexosaminidase resulting in GM2 ganglioside accumulation in brain. The purpose of this study was to delineate the natural history of the condition and identify genotype-phenotype correlations that might be helpful in predicting the course of the disease in individual patients.METHODS-A cohort of 21 patients with juvenile GM2 gangliosidosis, 15 with the Tay-Sachs variant and 6 with the Sandhoff variant, was studied prospectively in 2 centers. Our experience was compared with previously published reports on 134 patients. Information about clinical features, β-hexosaminidase enzyme activity, and mutation analysis was collected.RESULTS-In our cohort of patients, the mean (±SD) age of onset of symptoms was 5.3 ± 4.1 years, with a mean follow-up time of 8.4 years. The most common symptoms at onset were gait disturbances (66.7%), incoordination (52.4%), speech problems (28.6%), and developmental delay (28.6%). The age of onset of gait disturbances was 7.1 ± 5.6 years. The mean time for progression Address correspondence to Joe T. R. Clarke, MD, PhD, Division of Clinical and Metabolic Genetics, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. joe.clarke@sickkids.ca. The authors have indicated they have no financial relationships relevant to this article to disclose. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptto becoming wheelchair-bound was 6.2 ± 5.5 years. The mean age of onset of speech problems was 7.0 ± 5.6 years, with a mean time of progression to anarthria of 5.6 ± 5.3 years. Muscle wasting (10.6 ± 7.4 years), proximal weakness (11.1 ± 7.7 years), and incontinence of sphincters (14.6 ± 9.7 years) appeared later in the course of the disease. Psychiatric disturbances and neuropathy were more prevalent in patients with the Sandhoff variant than in those with the TaySachs variant. However, dysphagia, sphincter incontinence, and sleep problems occurred earlier in those with the Tay-Sachs variant. Cerebellar atrophy was the most common finding on brain MRI (52.9%). The median survival time among the studied and reviewed patients was 14.5 years. The genotype-phenotype correlation revealed that in patients with the Tay-Sachs variant, the presence of R178H and R499H mutations was predictive of an early onset and rapidly progressive course. The presence of either G269S or W474C mutations was associated with a later onset of symptoms along with a more slowly progressive disease course.CONCLUSIONS-Juvenile GM2 gangliosidosis is clinically heterogeneous, not only in terms of age of onset and clinical features but also with regard to the course of the disease. In general, the earlier the onset of symptoms, the more rapidly the disease progresses. The Tay-Sachs and Sandhoff variants differed somewhat in the frequency of specific clinical characteristics. Speech deterioration progressed more rapidly than gait abnormalities in both the Tay-Sa...

Neuromuscular synaptic transmission in aged ganglioside-deficient mice

“…in modulation of membrane-bound enzymes and ion-channels, cell-adhesion, neuritogenesis and membrane stability (Hakomori, 2003;Hashiramoto et al, 2006;Ledeen and Wu, 2006;Salazar et al, 2004;Sohn et al, 2006;Susuki et al, 2007;Wu et al, 2007;Yates and Rampersaud, 1998). Furthermore, anti-ganglioside autoimmunity and ganglioside turnover deficits cause neurological disorders (Ang et al, 2004;Maegawa et al, 2006;Simpson et al, 2004;Willison and Yuki, 2002).…”

Variante juvenil de la enfermedad de Sandhoff: presentación del primer caso descrito en Argentina

“…E n l o s últimos años, se han publicado 39 casos de e300 / Arch Argent Pediatr 2017;115(5):e298-e301 / Presentación de casos clínicos pacientes con diversos orígenes étnicos, entre ellos, paquistaníes, japoneses, brasileros, italianos, españoles, franceses, canadienses y estadounidenses. 4,[8][9][10][11][12][13][14][15] En Argentina, si bien existe la población endogámica con alta incidencia de ES infantil, hasta ahora, ningún paciente había tenido diagnóstico de ES juvenil. 3,6,7 Maegawa y col., en 2006, publicaron una revisión de la historia natural de las gangliosidosis GM2 variante juvenil (enfermedades de TaySachs y Sandhoff) y analizaron 21 casos nuevos y 134 pacientes previamente descritos en la bibliografía.…”

“…1,3 Variante juvenil: presenta gran heterogeneidad clínica; los primeros síntomas aparecen entre los 2 y los 10 años, y los más comunes son dificultades en la marcha, trastorno del habla, falta de coordinación y retraso global en el desarrollo. La muerte ocurre entre los 10 y 1,4 Variante adulta o crónica: existe una extremada variabilidad clínica; la aparición de síntomas es tardía y puede ocurrir entre la infancia y la adultez. Puede presentarse con distonía, degeneración espinocerebelosa, enfermedad de la motoneurona, alteraciones psiquiátricas, entre otras.…”

“…1,5 La ES es una patología poco frecuente en la población en general, con una incidencia estimada de 1 enfermo cada 422 000 individuos. 4 Sin embargo, esta enfermedad fue reconocida con alta incidencia en diferentes grupos étnicos, y se destaca la casuística de la comunidad criolla del Valle de Traslasierra de Córdoba y los llanos de La Rioja, Argentina. 3,6,7 En esta población endogámica, la frecuencia de portadores fue estimada en 1 cada 16-29 individuos y la incidencia de enfermos, de 131 x 10 -5 (100 000 nacimientos), equivalente a 1 enfermo cada 763 recién nacidos (RN).…”

Infantile Sandhoff Disease: Unusual presentation

“…1 The resultant accumulation of GM 2 ganglioside within both grey matter nuclei and myelin sheaths of the white matter results in eventual severe neuronal dysfunction and neurodegeneration. Disease progression is rapid, resulting in early death.…”