Health Related Quality of Life, Disability, and Pain in Alpha Mannosidosis

Borgwardt, Line; Guffon, Nathalie; Amraoui, Yasmina; Jones, Simon A.; Meırleır, Linda De; Lund, Allan Meldgaard; Gil‐Campos, Mercedes; Hout, J. M. P. van den; Tylki‐Szymańska, Anna; Geraci, Silvia; Ardigò, Diego; Cattaneo, Federica; Harmatz, Paul; Phillips, Dawn

doi:10.1177/2326409818796854

Cited by 4 publications

(1 citation statement)

References 22 publications

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“…1,2 The prevalence of AM is estimated to be 1 in 500 000 live births worldwide, and the disease is not specific to any gender or ethnic group. 1,3,4 The clinical variability of AM signs and symptoms is broad, and the disorder presents on a continuum of severity over a patient's life span, becoming more debilitating over time. Symptoms include mental retardation, motor function disturbances, speech and hearing impairments, progressive coarsening of facial features, recurrent infections, impaired immune response, skeletal abnormalities, muscular pain and/or weakness, and ocular changes.…”

Section: Introductionmentioning

confidence: 99%

Long‐term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha‐mannosidosis: A phase 2, open label, multicenter study

Guffon

Konstantopoulou

Hennermann

et al. 2023

J of Inher Metab Disea

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Alpha‐mannosidosis (AM) is a rare, autosomal recessive, lysosomal storage disorder caused by alpha‐mannosidase deficiency that leads to the accumulation of mannose‐rich oligosaccharides. AM symptoms and severity vary among individuals; consequently, AM is often not diagnosed until late childhood. Velmanase alfa (VA), a recombinant human lysosomal alpha‐mannosidase product, is the first enzyme replacement therapy indicated to treat non‐neurological symptoms of AM in Europe. Previous studies suggested that early VA treatment in children may produce greater clinical benefit over the disease course than starting treatment in adolescents or adults; however, long‐term studies in children are limited, and very few studies include children under 6 years of age. The present phase 2, multicenter, open‐label study evaluated the safety and efficacy of long‐term VA treatment in children under 6 years of age with AM. Five children (three males) received VA weekly for ≥24 months, and all children completed the study. Four children experienced adverse drug reactions (16 events) and two experienced infusion‐related reactions (12 events). Most (99.5%) adverse events were mild or moderate, and none caused study discontinuation. Four children developed antidrug antibodies (three were neutralizing). After VA treatment, all children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreases), hearing, immunological profile, and quality of life, suggesting a beneficial effect of early treatment. Although the small study size limits conclusions, these results suggest that long‐term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to patients with AM under 6 years of age.

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Section: Introductionmentioning

confidence: 99%

Long‐term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha‐mannosidosis: A phase 2, open label, multicenter study

Guffon

Konstantopoulou

Hennermann

et al. 2023

J of Inher Metab Disea

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Use of the Bruininks-Oseretsky test of motor proficiency (BOT-2) to assess efficacy of velmanase alfa as enzyme therapy for alpha-mannosidosis

Phillips

Hennermann

Tylki‐Szymańska

et al. 2020

Molecular Genetics and Metabolism Reports

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Molecular basis of neurocognitive dysfunction and psychosis in Alpha-Mannosidosis

Dewsbury,

Hargreaves,

Morgan

et al. 2024

J Transl Genet Genom

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A significant portion of patients who are afflicted with lysosomal storage diseases (LSDs) encounter neurological manifestations, including cognitive issues and developmental delay, seizures, psychiatric issues, and an overall neurodegenerative decline. In order to enhance the development of effective therapies for these symptoms, it is imperative that we allude to the neuropathophysiology that underlies these manifestations. These distinct neurological and developmental features are particularly evident in patients with Alpha-Mannosidosis (AM), a type of LSD. However, there is limited published information regarding the mechanisms and pathophysiology of these presentations in patients with this condition. Although the precise impact of lysosomal storage on the biogenesis and functioning of neuronal cells has not been clearly defined, recent studies have placed emphasis on the significance of synaptic defects influencing this dysfunction. These defects encompass changes in synaptic spines, proteins, and vesicles, as well as postsynaptic densities that potentially precipitate functional disruptions in synaptic transmission and neurodegeneration. Ultimately, this cascade is thought to result in extensive neuronal loss and, consequently, the onset of cognitive manifestations. Uncovering the effects on synaptic components in LSDs with neurological symptoms like AM will enable a better understanding of disease progression. It will also allow us to identify critical targets for therapeutic intervention and the determination of optimal time frames for targeted treatments, as well as the effects of these treatments on mitochondrial function. The available therapeutic modalities in AM are not a definitive cure for affected patients, but rather an attempt to reduce the symptomatic severity in their presentation, while aiming to regress/slow down disease progression. This review will aim to discuss and rationalize the current treatment approaches in place for AM patients in relation to their effects on the improvement of neurocognitive symptoms in affected AM individuals.

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Health Related Quality of Life, Disability, and Pain in Alpha Mannosidosis

Cited by 4 publications

References 22 publications

Long‐term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha‐mannosidosis: A phase 2, open label, multicenter study

Long‐term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha‐mannosidosis: A phase 2, open label, multicenter study

Use of the Bruininks-Oseretsky test of motor proficiency (BOT-2) to assess efficacy of velmanase alfa as enzyme therapy for alpha-mannosidosis

Molecular basis of neurocognitive dysfunction and psychosis in Alpha-Mannosidosis

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