Thalamic Changes in Tay-Sachs' Disease

Sharma, Suvasini; Sankhyan, Naveen; Kalra, Veena; Garg, Ajay

doi:10.1001/archneur.65.12.1669

Cited by 8 publications

(5 citation statements)

References 4 publications

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“…6 Renaud et al showed delayed myelination and hyperintensity of the posterior thalami in the region of the pulvinar nuclei. 7 Similar changes have been reported for classical gangliosidosis, especially in the basal ganglia, but also in the thalamus [8][9][10] as well as periventricular white matter. 11,12 These signs were also seen in our patients, both of which showed signal changes in the basal ganglia and some myelination delay: one showed signal changes of periventricular white matter and the other some signal changes of the posterior thalami at 14 months.…”

Section: Discussionsupporting

confidence: 74%

Rare Variant of GM2 Gangliosidosis through Activator-Protein Deficiency

et al. 2017

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GM2 gangliosidosis, AB variant, is a very rare form of GM2 gangliosidosis due to a deficiency of GM2 activator protein. We report on two patients with typical clinical features suggestive of GM2 gangliosidosis, but normal results for hexosaminidase A and hexosaminidase B as well as their corresponding genes. Genetic analysis of the gene encoding the activator protein, the gene, elucidated the cause of the disease, adding a novel mutation to the spectrum of GM2 AB variant. This report points out that in typical clinical constellations with normal enzyme results, genetic diagnostic for activator protein defects should be performed.

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Section: Discussionsupporting

confidence: 74%

Rare Variant of GM2 Gangliosidosis through Activator-Protein Deficiency

et al. 2017

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“…Chen et al (1999) describe abnormal MRI signal intensity in the periventricular white matter and basal ganglia in a patient with AB variant. The MRI in Tay-Sachs demonstrates diffuse dysmyelination of hemispheric white matter and bilateral symmetric signal change in the thalami with hyperintensity on T1 and hypointensity on T2 and FLAIR images (Sharma et al 2008). Magnetic resonance imaging of our patient at 17 months of age revealed delayed but interval myelination associated with abnormal signal Fig.…”

Section: Discussionmentioning

confidence: 58%

GM2-Gangliosidosis, AB Variant: Clinical, Ophthalmological, MRI, and Molecular Findings

Renaud

Brodsky

2015

JIMD Reports

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GM2-gangliosidosis, AB variant is a very rare form of GM2 gangliosidosis due to a deficiency of GM2 activator protein, associated with autosomal recessive mutations in GM2A. Less than ten patients, confirmed by molecular analysis, have been described in the literature.A 12-month-old Hmong girl presented to the neurometabolic clinic for evaluation of global developmental delay, hypotonia, and cherry red spots. The parents were not known to be consanguineous. Her examination was remarkable for hypotonia with hyperreflexia and excessive startling. The head circumference was normal. An extensive neurometabolic evaluation was negative.Developmental regression began at 14 months of age. Retinal examination at 16 months of age disclosed 4+ cherry red/black spots with "heaped up" ring of whitish infiltrate surrounding both foveae but no evidence of optic atrophy or peripheral retinal abnormalities. Repeat magnetic resonance imaging (MRI) scan at 17 months of age revealed delayed but interval myelination associated with abnormal signal intensity of the bilateral thalami presenting as T2 hyperintensity of the posterior thalami in the region of the pulvinar nuclei and T2 hypointensity in the anterior thalami. Sequencing of the GM2A gene revealed a homozygous c.160 G>T mutation, predicted to result in a premature protein termination p. Glu54*.

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“…Although this method carries potential risk of thalamic bleeding and/or thalamic pain syndrome, it is an efficient method for treating Tay-Sachs and Sandhoff disease in animals, 8,18,24,25 and is where pathology first occurs in humans. [30][31][32] In addition, direct injection of the thalamus is an attractive delivery location because it is highly interconnected to most of the brain where axonal transport markedly extends distribution, as evidenced by preclinical studies. 8,18,25,27 Animals have smaller brains than humans; therefore, translation requires a scale-up in injection volume and carries aforementioned inherent risks (cavity formation and/or prolonged anesthesia time).…”

Section: Discussionmentioning

confidence: 99%

Volume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model

et al. 2020

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Thalamic infusion of adeno-associated viral (AAV) vectors has been shown to have therapeutic effects in neuronopathic lysosomal storage diseases. Preclinical studies in sheep model of Tay-Sachs disease demonstrated that bilateral thalamic injections of AAV gene therapy are required for maximal benefit. Translation of thalamic injection to patients carries risks in that (1) it has never been done in humans, and (2) dosing scale-up based on brain weight from animals to humans requires injection of larger volumes. To increase the safety margin of this infusion, a flexible cannula was selected to enable simultaneous bilateral thalamic infusion in infants while monitoring by imaging and/or to enable awake infusions for injection of large volumes at low infusion rates. In this study, we tested various infusion volumes (200-800 lL) and rates (0.5-5 lL/min) to determine the maximum tolerated combination of injection parameters. Animals were followed for *1 month postinjection with magnetic resonance imaging (MRI) performed at 14 and 28 days. T1-weighted MRI was used to quantify thalamic damage followed by histopathological assessment of the brain. Trends in data show that infusion volumes of 800 lL (2 • the volume required in sheep based on thalamic size) resulted in larger lesions than lower volumes, where the long infusion times (between 13 and 26 h) could have contributed to the generation of larger lesions. The target volume (400 lL, projected to be sufficient to cover most of the sheep thalamus) created the smallest lesion size. Cannula placement alone did result in damage, but this is likely associated with an inherent limitation of its use in a small brain due to the length of the distal rigid portion and lack of stable fixation. An injection rate of 5 lL/min at a volume *1/3 of the thalamus (400-600 lL) appears to be well tolerated in sheep both clinically and histopathologically.

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Thalamic Changes in Tay-Sachs' Disease

Cited by 8 publications

References 4 publications

Rare Variant of GM2 Gangliosidosis through Activator-Protein Deficiency

Rare Variant of GM2 Gangliosidosis through Activator-Protein Deficiency

GM2-Gangliosidosis, AB Variant: Clinical, Ophthalmological, MRI, and Molecular Findings

Volume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model

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