Amyotrophy, cerebellar impairment and psychiatric disease are the main symptoms in a cohort of 14 Czech patients with the late-onset form of Tay–Sachs disease

Jahnová, Helena; Poupětová, Helena; Jirečková, Jitka; Vlášková, Hana; Košťálová, Eva; Mazanec, Radim; Zumrová, Alena; Mečíř, Petr; Mušová, Zuzana; Magner, Martin

doi:10.1007/s00415-019-09364-3

Cited by 22 publications

(30 citation statements)

References 16 publications

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“…atrophy of the cerebellum (Table 1). Notably, all 14/14 LOTS patients described by Jahnova et al as well as all 18/18 LOTS patients reported by Neudorfer et al exhibit the clinical finding of cerebellar atrophy [4,7].…”

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confidence: 87%

“…While the specific combination of the patient’s pathogenic variants in HEXA has to our knowledge not yet been described, the first variant c.508C>T was reported in association with the infantile course of TSD with a complete loss-of-function in in-vitro assays [ 6 ]. A detailed characterization of the second variant c.805G>A, has recently been described by Jahnova et al to provoke later-onset forms of disease owing to a residual HexA activity of 1.8–4.1% [ 7 ]. In a systemic Orphanet-survey performed in 2020 the overall birth prevalence of TSD was estimated at 0.28/100,000 [ 8 ].…”

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confidence: 99%

“…In a systemic Orphanet-survey performed in 2020 the overall birth prevalence of TSD was estimated at 0.28/100,000 [ 8 ]. Considering the limited number of patients carrying the c.805G>A variant in HEXA previously published, the presence of this specific variant within a cohort of 14 Czech LOTS patients is astonishing [ 7 ]. While a geographical clustering of the variant c.805G>A cannot be ruled out, the numbers suggest that TSD and especially its late-onset form (LOTS) still remain widely under- or misdiagnosed.…”

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confidence: 99%

“…as well as all 18/18 LOTS patients reported by Neudorfer et al . exhibit the clinical finding of cerebellar atrophy [ 4 , 7 ].…”

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confidence: 99%

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Cerebellar atrophy on top of motor neuron compromise as indicator of late-onset GM2 gangliosidosis

et al. 2021

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An 18-year-old-male of healthy non-consanguineous parents presented with slowly progressive muscle weakness. The onset of his clinical symptoms began at the age of 13 years with fatigue and muscle pain. 1 year later he complained about increasing walking difficulties. On physical examination the patient exhibited cachexia, dysarthria, scoliosis, generalized muscular atrophy, bilateral symmetric hyperreflexia, a mild ataxic gait as well as subtle bilateral action tremor. Electromyography revealed signs of diffuse denervation reminiscent of lower motor neuron degeneration or anterior horn disease. Magnetic resonance imaging (MRI) of the brain at the age of 16 years showed moderate diffuse cerebellar atrophy without supratentorial cerebral atrophy * Victoria Tüngler

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confidence: 87%

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confidence: 99%

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confidence: 99%

“…as well as all 18/18 LOTS patients reported by Neudorfer et al . exhibit the clinical finding of cerebellar atrophy [ 4 , 7 ].…”

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confidence: 99%

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Cerebellar atrophy on top of motor neuron compromise as indicator of late-onset GM2 gangliosidosis

et al. 2021

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“…A normal HexA protein will enable the hydrolysis of the GM2 ganglioside to produce the GM3 ganglioside. 8 It is thought that the accessory protein GM2 activator protein (GM2AP) first binds with GM2 and then pulls it out from the intralysosomal vesicles so that the headgroup of the GM2 ganglioside becomes accessible to HexA for hydrolysis. HexA is the only protein that has the capability to process GM2 ganglioside.…”

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confidence: 99%

In‐silico screening and microsecond molecular dynamics simulations to identify single point mutations that destabilize β‐hexosaminidase A causing Tay‐Sachs disease

2021

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β-hexosaminidase A (HexA) protein is responsible for the degradation of GM2 gangliosides in the central and peripheral nervous systems. Tay-Sachs disease occurs when HexA within Hexosaminidase does not properly function and harmful GM2 gangliosides begin to build up within the neurons. In this study, in silico methods such as SIFT, PolyPhen-2, PhD-SNP, and MutPred were utilized to analyze the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) on HexA in order to identify possible pathogenetic and deleterious variants. Molecular dynamics (MD) simulations showed that two mutants, P25S and W485R, experienced an increase in structural flexibility compared to the native protein. Particularly, there was a decrease in the overall number and frequencies of hydrogen bonds for the mutants compared to the wildtype. MM/GBSA calculations were performed to help assess the change in binding affinity between the wildtype and mutant structures and a mechanism-based inhibitor, NGT, which is known to help increase the residual activity of HexA. Both of the mutants experienced a decrease in the binding affinity from À23.8 kcal/mol in wildtype to À20.9 and À18.7 kcal/mol for the P25S and W485R variants of HexA, respectively.

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Clinical Aspects and Clinical Diagnosis

Beck¹

2022

Lysosomal Storage Disorders

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Amyotrophy, cerebellar impairment and psychiatric disease are the main symptoms in a cohort of 14 Czech patients with the late-onset form of Tay–Sachs disease

Cited by 22 publications

References 16 publications

Cerebellar atrophy on top of motor neuron compromise as indicator of late-onset GM2 gangliosidosis

Cerebellar atrophy on top of motor neuron compromise as indicator of late-onset GM2 gangliosidosis

In‐silico screening and microsecond molecular dynamics simulations to identify single point mutations that destabilize β‐hexosaminidase A causing Tay‐Sachs disease

Clinical Aspects and Clinical Diagnosis

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