The juvenile gangliosidoses: A timeline of clinical change

King, Kelly; Kim, Sarah; Whitley, Chester B.; Jarnes-Utz, Jeanine R.

doi:10.1016/j.ymgmr.2020.100676

Cited by 9 publications

(28 citation statements)

References 17 publications

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“…We found that dysarthria and gait ataxia are the most common clinical signs, seen in 96.5% and 93.1% of the cases, respectively. [ 3 5 6 7 8 9 ] In the present case also, there was a similar observation with an additional sign of bilateral tremors in hand at 5 years of age which has been seen in only 26.72% of the previously reported cases. [ 3 ] The MRI findings showing cortical atrophy in our case are consistent with those observed in other juvenile TSD cases.…”

supporting

confidence: 88%

Juvenile Tay Sachs Disease Due to Compound Heterozygous Mutation in Hex-A Gene, with Early Sign of Bilateral Tremors

Sheth¹,

Mohapatra²,

Patra³

et al. 2022

Annals of Indian Academy of Neurology

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supporting

confidence: 88%

Juvenile Tay Sachs Disease Due to Compound Heterozygous Mutation in Hex-A Gene, with Early Sign of Bilateral Tremors

Sheth¹,

Mohapatra²,

Patra³

et al. 2022

Annals of Indian Academy of Neurology

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“…Would dosing earlier in disease course, when less neurological damage has occurred, allow for a better therapeutic response? King et al [ 3 ] has described a timeline of clinical changes that occur in the infantile and juvenile gangliosidoses through a clinical perspective natural history study. The gangliosidoses are chronically progressive, but a critical window of time exists in which the patients do not show overt signs of their gangliosidosis condition.…”

Section: Discussionmentioning

confidence: 99%

“…Signs of disease leading caregivers to seek a diagnosis typically do not occur until after the third to fifth year of life, and most often initially present as changes in ambulation skills and language skills. In an intermediate form, the late-infantile phenotype, patients meet first-year development milestones, followed by appearance of marked changes in ambulation and language skills [ 3 ]. Considering the severe and progressive neurological impairment that occurs in the gangliosidoses and concerns about irreversibility of neurological damage, an effective therapy may require therapy initiation to occur early, before disease symptoms are apparent.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with the late-infantile and juvenile phenotypes usually learn to walk, but develop ataxia in early childhood and eventually become non-ambulatory. Death commonly occurs in early to mid-childhood in the late-infantile phenotype and in mid- to late-childhood in the juvenile phenotype [ 3 ]. Currently, there are no clinically approved treatments for GM1-gangliosidosis.…”

Section: Introductionmentioning

confidence: 99%

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Examination of a blood-brain barrier targeting β-galactosidase-monoclonal antibody fusion protein in a murine model of GM1-gangliosidosis

Przybilla

Stewart

Carlson

et al. 2021

Molecular Genetics and Metabolism Reports

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GM1-gangliosidosis is a lysosomal disease resulting from a deficiency in the hydrolase β-galactosidase (β-gal) and subsequent accumulation of gangliosides, primarily in neuronal tissue, leading to progressive neurological deterioration and eventually early death. Lysosomal diseases with neurological involvement have limited non-invasive therapies due to the inability of lysosomal enzymes to cross the blood-brain barrier (BBB). A novel fusion enzyme, labeled mTfR-GLB1, was designed to act as a ferry across the BBB by fusing β-gal to the mouse monoclonal antibody against the mouse transferrin receptor and tested in a murine model of GM1-gangliosidosis (β-gal −/− ). Twelve hours following a single intravenous dose of mTfR-GLB1 (5.0 mg/kg) into adult β-gal −/− mice showed clearance of enzyme activity in the plasma and an increase in β-gal enzyme activity in the liver and spleen. Long-term efficacy of mTfR-GLB1 was assessed by treating β-gal −/− mice intravenously twice a week with a low (2.5 mg/kg) or high (5.0 mg/kg) dose of mTfR-GLB1 for 17 weeks. Long-term studies showed high dose mice gained weight normally compared to vehicle-treated β-gal −/− mice, which are significantly heavier than heterozygous controls. Behavioral assessment at six months of age using the pole test showed β-gal −/− mice treated with mTfR-GLB1 had improved motor function. Biochemical analysis showed an increase in β-gal enzyme activity in the high dose group from negligible levels to 20% and 11% of heterozygous levels in the liver and spleen, respectively. Together, these data show that mTfR-GLB1 is a catalytically active β-gal fusion enzyme in vivo that is readily taken up into tissues. Despite these indications of bioactivity, behavior tests other than the pole test, including the Barnes maze, inverted screen, and accelerating rotarod, showed limited or no improvement of treated mice compared to β-gal −/− mice receiving vehicle only. Further, administration of mTfR-GLB1 was insufficient to create measurable increases in β-gal enzyme activity in the brain or reduce ganglioside content (biochemically and morphologically).

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“…Pathologically, multiple brain regions including caudate, putamen, corpus callosum, basal ganglia, and cerebellar white matter are atrophied ( Nestrasil et al, 2018 ). MRI scans and postmortem brain analyses revealed hypomyelination and atrophy of the caudate, putamen, corpus callosum, and basal ganglia ( King et al, 2020 ; Uchino et al, 2020 ).…”

Section: Lysosomal Lipid Metabolism and Catabolism Defectsmentioning

confidence: 99%

Emerging cellular themes in leukodystrophies

Nowacki

Fields

2022

Front. Cell Dev. Biol.

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Leukodystrophies are a broad spectrum of neurological disorders that are characterized primarily by deficiencies in myelin formation. Clinical manifestations of leukodystrophies usually appear during childhood and common symptoms include lack of motor coordination, difficulty with or loss of ambulation, issues with vision and/or hearing, cognitive decline, regression in speech skills, and even seizures. Many cases of leukodystrophy can be attributed to genetic mutations, but they have diverse inheritance patterns (e.g., autosomal recessive, autosomal dominant, or X-linked) and some arise from de novo mutations. In this review, we provide an updated overview of 35 types of leukodystrophies and focus on cellular mechanisms that may underlie these disorders. We find common themes in specialized functions in oligodendrocytes, which are specialized producers of membranes and myelin lipids. These mechanisms include myelin protein defects, lipid processing and peroxisome dysfunction, transcriptional and translational dysregulation, disruptions in cytoskeletal organization, and cell junction defects. In addition, non-cell-autonomous factors in astrocytes and microglia, such as autoimmune reactivity, and intercellular communication, may also play a role in leukodystrophy onset. We hope that highlighting these themes in cellular dysfunction in leukodystrophies may yield conceptual insights on future therapeutic approaches.

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The juvenile gangliosidoses: A timeline of clinical change

Cited by 9 publications

References 17 publications

Juvenile Tay Sachs Disease Due to Compound Heterozygous Mutation in Hex-A Gene, with Early Sign of Bilateral Tremors

Juvenile Tay Sachs Disease Due to Compound Heterozygous Mutation in Hex-A Gene, with Early Sign of Bilateral Tremors

Examination of a blood-brain barrier targeting β-galactosidase-monoclonal antibody fusion protein in a murine model of GM1-gangliosidosis

Emerging cellular themes in leukodystrophies

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