Spontaneous improvement of carbohydrate-deficient transferrin in PMM2-CDG without mannose observed in CDG natural history study

Abstract

A recent report on long-term dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) claimed improved glycosylation and called for double-blind randomized study of the dietary supplement in PMM2-CDG patients. A lack of efficacy of short-term mannose supplementation in multiple prior reports challenge this study’s conclusions. Additionally, some CDG types have previously been reported to demonstrate spontaneous improvement in glycosylated biomarkers, including transferrin. We have likewise observed improvements in transferrin glycosylation without mannose supplementation. This observation questions the reliability of transferrin as a therapeutic outcome measure in clinical trials for PMM2-CDG. We are concerned that renewed focus on mannose therapy in PMM2-CDG will detract from clinical trials of more promising therapies. Approaches to increase efficiency of clinical trials and ultimately improve patients’ lives requires prospective natural history studies and identification of reliable biomarkers linked to clinical outcomes in CDG. Collaborations with patients and families are essential to identifying meaningful study outcomes.

Normal transferrin glycosylation does not rule out severe ALG1 deficiency

“…However, the possibility of spontaneous improvement in transferrin glycosylation in young PMM2-CDG patients is known. 34 Based on our literature review, 86 patients have been described since the discovery of the disease and only one of them showed a normal transferrin glycosylation. (Table 1).…”

“…Although the serum transferrin profile could be normal in the first weeks of life in CDG patients 32 or CDG patients with Golgi disruption 33 this has been reported abnormal in ALG1‐CDG patients in early childhood. However, the possibility of spontaneous improvement in transferrin glycosylation in young PMM2‐CDG patients is known 34 …”

Chemical Therapies for Congenital Disorders of Glycosylation

“…Intravenous mannose treatment in a single PMM2-CDG individual was also not effective . Moreover, the most recent research demonstrates that glycosylation of TF spontaneously improves with time in multiple PMM2-CDG subjects . Recently, in a pilot trial, of oral galactose therapy in PMM-CDG was conducted, as this treatment had been successfully applied to a few other CDG (described in detail in the next section).…”

“…15 Moreover, the most recent research demonstrates that glycosylation of TF spontaneously improves with time in multiple PMM2-CDG subjects. 16 Recently, in a pilot trial, of oral galactose therapy in PMM-CDG was conducted, as this treatment had been successfully applied to a few other CDG (described in detail in the next section). Overall, oral galactose therapy did not result in significant improvement, but the authors claim some milder subjects showed positive clinical changes with a trend toward improved TF glycosylation.…”

Mannose supplementation in PMM2-CDG

“…The letter by Witters et al relates to our recent publication on long-term mannose supplementation, a paper that did not summarize data of a prospective clinical study but analyzed data obtained by long-term care for PMM2 patients [ 1 , 2 ]. Many of their arguments had already been discussed in our paper and our response is lined out in the following addresses the critical points.…”