Pediatric sleep disorders are common and costly: how can we help?

The GM2 gangliosidoses are rare autosomal recessive lysosomal storage disorders caused by the accumulation of GM2 ganglioside due to the absence or near absence of ß-hexosamindase A (EC 3.1.2.52), the heterodimeric enzyme that degrades glycosphingolipid GM2 in healthy tissue of unaffected individuals. Pathological accumulation of GM2 ganglioside unleashes a cascade of events leading to progressive neurodegeneration [,]. Tay-Sachs and Sandhoff diseases are the predominate forms of GM2 gangliosidosis with a prevalence of 1 in 200,000–320,000 and 1:500,000–1,500,000 individuals, respectively [–] An additional ultrarare form caused by biallelic variants in , encodes the GM2, the activator protein required for GM2 degradation []. The prevalence of Tay-Sachs disease is higher among the Ashkenazi Jewish and non-Jewish French Canadians from southeastern Quebec due to founder effects [, –]. Tay-Sachs disease (OMIM #272800) is caused by biallelic pathogenic mutations in , encoding the alpha subunit of ß-hexosaminidase A, while Sandhoff disease (OMIM #268800) is caused by biallelic pathogenic mutations in , which encodes the beta subunit of ß-hexosaminidase A [, ,]. Both Tay-Sachs and Sandhoff diseases are a continuum of disease severity classified into infantile, juvenile, and late-onset (adult) forms based on the timing of symptom onset approximately correlated with residual ß-hexosaminidase A activity [,]. The infantile forms of these diseases are the most severe with symptom onset occurring before six months and death by five years of age [,]. The juvenile form of these diseases is less severe with symptom onset between 2 and 6 years of age and death resulting within the second decade. The adult or late-onset form of Tay-Sachs or Sandhoff diseases are the most heterogeneous, with symptom onset beginning during adolescence or early adulthood and life expectancy slightly reduced compared to unaffected individuals [–]. There is no targeted treatment for the GM2 gangliosidoses; however, trials of gene therapy and the modified amino acid -acetyl-L-leucine (NALL) have been recently reported [,]. Patients with late-onset GM2 present with neuromuscular weakness, cerebellar dysfunction, and/or psychiatric symptoms [,]. There is substantial heterogeneity in presenting symptoms and disease progression of patients, even among siblings sharing the same mutations and genetic background [–]. Neurodegeneration is inexorably progressive over decades with worsening weakness, incoordination, dysarthria, and, in the later stages of the disease, cognitive dysfunction [, ,]. Late-onset Tay-Sachs (LOTS) and late-onset Sandhoff disease (LOSD) have long been considered clinically identical. However, some phenotypic features of LOTS and LOSD appear more prevalent in one form over the other. For example, psychosis is more characteristic of LOTS while early sensory symptoms seem to be more pronounced in LOSD []. Pure cerebellar dysfunction and dysarthria may be more severe in LOTS [,]. However, weakness and ambulation difficulties are common to both []. Strength testing on physical examination shows earlier involvement in the lower limbs, more specifically in the hip flexor and knee extensor muscles with later progression to the upper limbs, involving primarily the triceps. Electrophysiological studies indicate neurogenic weakness consistent with an anterior horn neuronopathy, a shared phenotype of LOTS and LOSD [].