Would, early, versus late hydroxocobalamin dose intensification treatment, prevent cognitive decline, macular degeneration and ocular disease, in 5 patients with early-onset cblC deficiency?

Emmanuel Scalais; Christine Geron; Charlotte Pierron; Sandra Cardillo; Vincent Schlesser; Frédéric Mataigne; Patricia Borde; Luc Regal

doi:10.1016/j.ymgme.2023.107681

Would, early, versus late hydroxocobalamin dose intensification treatment, prevent cognitive decline, macular degeneration and ocular disease, in 5 patients with early-onset cblC deficiency?

Mol Genet Metab. 2023 Nov;140(3):107681. doi: 10.1016/j.ymgme.2023.107681. Epub 2023 Aug 11.

Authors

Emmanuel Scalais¹, Christine Geron², Charlotte Pierron², Sandra Cardillo³, Vincent Schlesser⁴, Frédéric Mataigne⁵, Patricia Borde⁶, Luc Regal⁷

Affiliations

¹ Department of Pediatrics, Division of Pediatric Neurology, Centre Hospitalier de Luxembourg, Luxembourg. Electronic address: emmanuel.Scalais@gmail.com.
² Department of Pediatrics, Neonatal Center, Pediatric Intensive Care, Centre Hospitalier de Luxembourg, Luxembourg.
³ Service d'Ophtalmologie, Centre Hospitalier de Luxembourg, Luxembourg.
⁴ Laboratoire de Chimie et Hématologie, Centre Hospitalier de Luxembourg, Luxembourg.
⁵ Service de Neuroradiologie, Centre Hospitalier de Luxembourg, Luxembourg.
⁶ Service de Biochimie, Laboratoire National de Santé, Dudelange, Luxembourg.
⁷ Pediatric Neurology and Metabolism, UZ, VUB, Vrije Universiteit Brussels, Brussels, Belgium.

PMID: 37604084
DOI: 10.1016/j.ymgme.2023.107681

Abstract

In early-onset (EO) cblC deficiency (MMACHC), hydroxocobalamin dose-intensification (OHCBL-DI) improved biochemical and clinical outcome. In mammals, Cobalamin is reduced, in a reaction mediated by MMACHC. Pathogenic variants in MMACHC disrupt the synthesis pathway of methyl-cobalamin (MetCbl) and 5'-deoxy-adenosyl-cobalamin (AdoCbl), cofactors for both methionine synthase (MS) and methyl-malonyl-CoA mutase (MCM) enzymes. In 5 patients (pts.), with EO cblC deficiency, biochemical and clinical responses were studied following OHCbl-DI (mean ± SD 6,5 ± 3,3 mg/kg/day), given early, before age 5 months (pts. 1, 2, 3 and 4) or lately, at age 5 years (pt. 5). In all pts., total homocysteine (tHcy), methyl-malonic acid (MMA) and Cob(III)alamin levels were measured. Follow-up was performed during 7^4/12 years (pts. 1, 2, 3), 3^3/12 years (pt. 4) and 3^4/12 years (pt. 5). OHCbl was delivered intravenously or subcutaneously. Mean ± SD serum Cob(III)alamin levels were 42,2 × 10⁶ ± 28, 0 × 10⁶ pg/ml (normal: 200-900 pg/ml). In all pts., biomarkers were well controlled. All pts., except pt. 5, who had poor vision, had central vision, mild to moderate nystagmus, and with peri-foveolar irregularity in pts. 1, 2 and 4, yet none had the classic bulls' eye maculopathy and retinal degeneration characteristic of pts. with EO cblC deficiency. Only pt. 5, had severe cognitive deficiency. Both visual and cognitive functions were better preserved with early than with late OHCBL-DI. OHCBL-DI is suggested to bypass MMACHC, subsequently to be rescued by methionine synthase reductase (MSR) and adenosyl-transferase (ATR) to obtain Cob(I)alamin resulting in improved cognitive and retinal function in pts. with EO cblC deficiency.

Keywords: Cobalamin; Cytosolic methionine synthase; Homocysteine; Methylmalonic acid; Mitochondrial methylmalonyl-CoA mutase; Oxidant defense hypothesis; Rescue enzymes; electron transfer.

MeSH terms

Child, Preschool
Cognitive Dysfunction* / drug therapy
Homocystinuria* / drug therapy
Homocystinuria* / genetics
Humans
Hydroxocobalamin / therapeutic use
Infant
Macular Degeneration* / drug therapy
Male
Mammals
Oxidoreductases
Vitamin B 12 / metabolism
Vitamin B 12 Deficiency* / drug therapy

Substances

Hydroxocobalamin
MMACHC protein, human
Oxidoreductases
Vitamin B 12