The Natural History of Cognitive Dysfunction in Late-Onset GM2 Gangliosidosis

Abstract

Background: Late-onset GM 2 gangliosidosis (LGG) is a rare disease that is often considered in the differential diagnosis of adolescents and young adults who present with multiple realms of neurologic dysfunction. Cognitive disturbances are common but have not been systematically studied. Objective: To determine the natural history of cognitive dysfunction in patients with LGG.

Multi-system disorders of glycosphingolipid and ganglioside metabolism

“…However, a recent glucosylsphingosine storage disease mouse model supports this concept ( 205 ). The correlations between disease progression and age-dependent GSL levels also occur in NPC disease ( 206 ), Tay-Sachs disease ( 207 ), and GM1 gangliosidosis mice ( 156 ).…”

Early deficits in motor coordination and cognitive dysfunction in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease

“…Sandhoff disease arises from defects in the gene encoding the β-subunit (hexb) of β-Nacetyl-d-hexosaminide N-acetylhexosaminohydrolase (EC 3.2.1.52) normally involved in the sequential catabolism of gangliosides and other glycoconjugates [11]. Sandhoff patients have widespread brain pathology which results in clinical symptoms including progressive mental and motor deterioration [10,11,21].…”

“…Sandhoff disease arises from defects in the gene encoding the β-subunit (hexb) of β-Nacetyl-d-hexosaminide N-acetylhexosaminohydrolase (EC 3.2.1.52) normally involved in the sequential catabolism of gangliosides and other glycoconjugates [11]. Sandhoff patients have widespread brain pathology which results in clinical symptoms including progressive mental and motor deterioration [10,11,21].Two transgenic murine models of Sandhoff disease exist [23,25] that, like the human equivalent, exhibit premature death and display widespread neuronal storage of ganglioside, in addition to gliotic and inflammatory reactions and neuronal cell death [11,16,23,25,27]. The Sandhoff models have engendered much research directed at overcoming the challenges [1,2,4,11,14,15,18,20].…”

“…Much of the preclinical research is currently focused on molecular aspects and gross neurological symptoms. However, these human disorders can present with a complex behavioral phenotype including psychosis, mood disorders and cognitive impairment [10,11,21] and such aspects have rarely been addressed in murine models. In the present study with a Sandhoff disease model we found for the first time evidence of cognitive deficits in a memory task, and increased thigmotaxis in an open field test.…”

Late‐onset Tay–Sachs disease: The spectrum of peripheral neuropathy in 30 affected patients

“…In the chronic GM2-gangliosidoses, damage to nerve cells occurs when GM2-ganglioside accumulates within lysosomes, forming membranous cytoplasmic bodies (MCBs) or other cytoplasmic inclusions within nerve cells of the brain and spinal cord. In the late-onset Tay-Sachs variant (referred to as LOTS), patients present in childhood, adolescence, or early adulthood with dysfunction in one or more of the following domains: anterior horn cell (weakness, atrophy, cramps, fasciculations) 6,8,11 ; cerebellum (ataxia, dysarthria, dysmetria, dysdiadochokinesia, postural/intention tremor) 6,8,11 ; psychiatric (bipolar disorder, depression, schizophrenia) 14 ; cognitive (dementia) 4,18 ; pyramidal system (hypereflexia, spasticity); and extrapyramidal system (dystonia).…”