Parenteral hydroxocobalamin dose intensification in five patients with different types of early onset intracellular cobalamin defects: Clinical and biochemical responses.

Emmanuel Scalais,Patricia Borde,Hilde Laeremans,Vincent Schlesser,Charlotte Pierron,Elise Osterheld,Ronit Chafai,Linda De Meirleir,Koen L I Van Gassen,Luc Regal,L Bert Van Den Heuvel,Christine Geron

doi:10.1002/jmd2.12055

Abstract

Intracellular cobalamin metabolism (ICM) defects can be present as autosomal recessive or X‐linked disorders. Parenteral hydroxocobalamin (P‐OHCbl) is the mainstay of therapy, but the optimal dose has not been determined. Despite early treatment, long‐term complications may develop. We have analyzed the biochemical and clinical responses in five patients with early onset of different types of ICM defects (cblC: patients 1‐3; cblA: patient 4; cblX: patient 5) following daily P‐OHCbl dose intensification (DI). In patient 4, P‐OHCbl was started at age 10 years and in patient 5 at age 5 years. OHCbl was formulated at either, 5, 25, or 50 mg/mL. P‐OHCbl was intravenously or subcutaneously (SQ) delivered, subsequently by placement of a SQ injection port except in patient 4. In all patients, homocysteine and methylmalonic acid levels, demonstrated an excellent response to various P‐OHCbl doses. After age 36 months, patients 1‐3 had a close to normal neurological examination with lower range developmental quotient. In patient 3, moderate visual impairment was present. Patient 4, at age 10 years, had normal renal, visual and cognitive function. In cblX patient 5, epilepsy was better controlled. In conclusion, P‐OHCbl‐DI caused an excellent control of metabolites in all patients. In the three cblC patients, comparison with patients, usually harboring identical genotype and similar metabolic profile, was suggestive of a positive effect, in favor of clinical efficacy. With P‐OHCbl‐DI, CblA patient has been placed into a lower risk to develop renal and optic impairment. In cblX patient, lower P‐OHCbl doses were administrated to improve tolerability.

Highlights

Autosomal recessive disorders of intracellular cobalamin metabolism (ICM), designated as cblA-cblJ,[1] can give rise, either to a deficiency of methylmalonyl-CoA mutase resulting in isolated methylmalonic aciduria, or to a deficiency of methionine synthase resulting in isolated homocystinuria or to both, resulting in combined methylmalonic aciduria and homocystinuria
Despite representing a broader neurodevelopmental phenotype, severe MMACHC downregulation has been observed in cblX patients.15The aim of this study was to evaluate the clinical and biochemical response of P-OHCbl-dose intensification (DI) in patients with different types of early onset (EO) ICM defects, including Cobalamin C (cblC), cblA, and cblX
Compared to cblC patients 1 and 2, cblC patient 3, initially required higher OHCbl doses, to control plasma total homocysteine (tHcy) values. This discrepancy could be related to disease severity, including hemolytic-uremic syndrome (HUS), multiorgan failure, metabolic acidosis and poor perfusion

Summary

| INTRODUCTION

Autosomal recessive disorders of intracellular cobalamin metabolism (ICM), designated as cblA-cblJ,[1] can give rise, either to a deficiency of methylmalonyl-CoA mutase (cblA, cblB, and cblD variant 2) resulting in isolated methylmalonic aciduria, or to a deficiency of methionine synthase (cblD variant 1, cblE, and cblG) resulting in isolated homocystinuria or to both, (cblC, classic cblD, cblF, and cblJ), resulting in combined methylmalonic aciduria and homocystinuria. At age 3 weeks, both plasma total homocysteine (tHcy) and urinary methylmalonic acid (uMMA) values were elevated Both infants were treated (day one) with P-OHCbl (0.31 mg/kg/day) supplemented with oral betaine (100 mg/kg/day), folinic acid (5 mg/day), and oral L-carnitine (50 mg/kg/day), which was followed by clinical improvement. At age 3 weeks, cblC patient 3, a boy, presented anorexia and peri-orificial dermatitis He was admitted at age 27 days with multi-organ failure and metabolic acidosis (anion gap: 21 mmol/L, normal 8-16). Patient 5, a boy, previously reported,[24] showed, at age 10 days, refractory seizures and high CSF glycine mimicking non-ketotic hyperglycinemia Both urinary methylmalonic acid and plasma homocysteine were elevated. At age 7 years, following a very slow increase in P-OHCbl doses, as shown in Figure 1J,K, a better improvement in seizure control was obtained, but not in neurological development. Macrocytosis, less marked, was still present (MCV 99.5 μ3 vs 105.4 and 106.6, normal 76-91) suggesting that his P-OHCbl dose was not yet sufficient

| DISCUSSION

Findings

CONFLICT OF INTEREST