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Cobalamin C (Cbl-C) defects are inherited autosomal recessive disorders of vitamin B12 (or cyanocobalamin [CNCbl]) metabolism. These defects are caused by mutations in the methylmalonic aciduria and homocystinuria Cbl-C type (MMACHC; MIM # 609831) gene located on chromosome 1p34.1, which catalyzes the reductive decyanation of CNCbl, thus impairing the biosynthesis of 5'-deoxyadenosylcobalamin, adenosylcobalamin, and methylcobalamin. This impairment results in methylmalonic acidemia [MMA; MIM # 277400] combined with hyperhomocysteinemia and hypomethioninemia. Clinically, Cbl-C defects are characterized by a constellation of systemic signs and symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy, are common in the early-onset form of the disease, but are rare in its adult-onset counterpart. Administration of hydroxocobalamin (OHCbl), betaine, and folinic acid represents main therapeutic approaches. No proven efficacy has been demonstrated for carnitine and dietary protein restrictions. Although early introduction of OHCbl is crucial, no standardized protocols regarding dose adjustment exist. Despite these measures, the long-term outcome is unsatisfactory especially in patients with early onset, who experience frequent progression of their neurological and ocular impairment. The unfavorable outcome suggests that a better understanding of the pathophysiology of the disease is needed to improve treatment protocols and to develop new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Alpha-mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha-mannosidase deficiency and accumulation of mannose-rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase, is the first enzyme replacement therapy for non-neurological symptoms of AM. Previously, a potential relationship was identified between three MAN2B1 genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA-treated patients with AM, it is unknown if a relationship exists between MAN2B1 genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion-related reactions (IRRs). This pooled analysis evaluated data from 33 VA-treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment-emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment-emergent ADA-positive patients with relatively high titers ( n  = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well-managed; patients with lower titers ( n  = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA-positive and ADA-negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between MAN2B1 genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM., Competing Interests: Line Gutte Borgwardt has received consulting fees from Chiesi, the sponsor of the study; Ferdinando Ceravolo was an employee of Chiesi Farmaceutici S.p.A., the sponsor of the study; Giulia Zardi has received consulting fees from Chiesi Farmaceutici S.p.A., the sponsor of the study; Andrea Ballabeni is an employee of Chiesi Farmaceutici S.p.A., the sponsor of the study; Allan Meldgaard Lund has received consulting fees and/or honoraria/travel support from Amicus, BioMarin, Chiesi, Sanofi Genzyme, Shire/Takeda, Recordati, and Sobi as well as grant/research support from Sanofi Genzyme and Shire/Takeda., (© 2022 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Therapeutic plasma exchange, consisting of removing blood plasma and exchanging it with donated blood products, has been proposed for treating Alzheimer's disease (AD) to remove senescent or toxic factors. In preclinical studies, administration of plasma from young healthy mice to AD transgenic mice improved cognitive deficits without affecting brain amyloid plaques. Initial encouraging results have been collected in a double-blind, placebo-controlled study in nine AD patients receiving young plasma. In a 14-month double-blind, placebo-controlled study in 322 AD patients, multiple infusions with plasma enriched with albumin with or without immunoglobulins slowed cognitive, functional, and clinical decline, especially in moderately affected patients. Clinical trials of plasma fractions containing hypothetically beneficial proteins are also under way. These initial positive clinical results need to be confirmed in larger and more rigorous controlled studies in which the possible benefits of plasma exchange approaches can be weighed against the intrinsic side effects of repetitive infusion procedures., Competing Interests: Bruno P. Imbimbo (PhD) is an employee at Chiesi Farmaceutici. He is listed among the inventors of a number of Chiesi Farmaceutici's patents of anti‐Alzheimer drugs. Stefania Ippati (PhD), Ferdinando Ceravolo (MD), and Mark Watling (MD) have no conflict of interest to declare., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)