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

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′-deoxyadenosyl-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 74/12 years (pts. 1, 2, 3), 33/12 years (pt. 4) and
34/12 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 adenosyltransferase (ATR) to obtain Cob(I)alamin resulting in improved cognitive and retinal function in pts. with EO
cblC deficiency.